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\begin{document}

\title{Stem cell therapy in pulmonary arterial hypertension: current practice
and future opportunities}



\author[1]{Ruixuan Zheng}%
\author[1]{Mengyao Xie}%
\author[1]{Xinghong Wang}%
\author[1]{Lehe Yang}%
\author[2]{Jian Wang}%
\author[1]{xiaoying huang}%
\affil[1]{The First Affiliated Hospital of Wenzhou Medical University}%
\affil[2]{University of California San Diego}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Pulmonary arterial hypertension (PAH) is a chronic disease that is
characterized as mean pulmonary artery hypertension (mPAP)
\textgreater{} 25 mmHg. PAH is caused by progressive obliteration of
small pulmonary arteries due to known or unknown etiologies. The effect
of traditional therapy is suboptimal because it can only improve
symptoms but cannot cure the disease, and therefore, scientists have
turned their attention to stem cell therapy for efficacious treatments.
In recent years, accumulating evidences have demonstrated that
endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs)
are closely related with the occurrence of PAH and have the ability to
prevent and reverse this disease. In this review, we turn our attention
to a novel therapy for PAH, stem cell therapy, through comparing effect
of preclinical research on cells and animals and evaluating the
feasibility and potential difficulties of clinical application.%
\end{abstract}%



\sloppy


\textbf{Stem cell therapy in pulmonary arterial hypertension: current
practice and future opportunities}

Ruixuan Zheng\textsuperscript{1,\#}, Mengyao Xie\textsuperscript{1,\#},
Xinghong Wang\textsuperscript{1}, Lehe Yang\textsuperscript{1,*}, Jian
Wang\textsuperscript{2,*}, Xiaoying Huang\textsuperscript{1,*}

\textsuperscript{1} Division of Pulmonary Medicine, The First Affiliated
Hospital, Wenzhou Medical University, Key Laboratory of Heart and Lung,
Wenzhou, Zhejiang 325000, China.

\textsuperscript{2} State Key Laboratory of Respiratory Disease,
National Clinical Research Center for Respiratory Disease, Guangdong Key
Laboratory of Vascular Disease, Guangzhou Institute of Respiratory
Health, the First Affiliated Hospital of Guangzhou Medical University,
Guangzhou, Guangdong, China

\textsuperscript{\#} These authors contribute equally to this work.

*Correspondence to:

Xiaoying Huang Professor and Lehe Yang Ph.D.

Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou
Medical University, Wenzhou, Zhejiang 325000, China.

mail: \emph{huangxiaoying@wzhospital.cn} and yanglehe@wmu.edu.com

Jian Wang Professor

State Key Laboratory of Respiratory Disease, National Clinical Research
Center for Respiratory Disease, Guangdong Key Laboratory of Vascular
Disease, Guangzhou Institute of Respiratory Health, the First Affiliated
Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou,
Guangdong 510120, China.

E-mail: \emph{jiw037@ucsd.edu}

Word count: 5411 words

\textbf{Abstract}

Pulmonary arterial hypertension (PAH) is a chronic disease that is
characterized as mean pulmonary artery hypertension (mPAP)
\textgreater{} 25 mmHg. PAH is caused by progressive obliteration of
small pulmonary arteries due to known or unknown etiologies. The effect
of traditional therapy is suboptimal because it can only improve
symptoms but cannot cure the disease, and therefore, scientists have
turned their attention to stem cell therapy for efficacious treatments.
In recent years, accumulating evidences have demonstrated that
endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs)
are closely related with the occurrence of PAH and have the ability to
prevent and reverse this disease. In this review, we turn our attention
to a novel therapy for PAH, stem cell therapy, through comparing effect
of preclinical research on cells and animals and evaluating the
feasibility and potential difficulties of clinical application.

\textbf{Key words:} stem cell, pulmonary arterial hypertension,
mesenchymal stem cell, endothelial progenitor cell, therapy

\textbf{Introduction}

Pulmonary arterial hypertension (PAH) is a chronic disease that is
characterized as mean pulmonary artery hypertension (mPAP)\textgreater{}
25 mmHg(Southgate, Machado, Graf, \& Morrell, 2020). According to an
investigation by the World Health Organization (WHO), the morbidity of
PAH is approximately 1\% for the world population, which equals
approximately 100 million deaths(Schermuly, Ghofrani, Wilkins, \&
Grimminger, 2011). For people over 65 years of age, this number
significantly increases to 10\%, and a statistic of concern is that more
than 80\% of patients with PAH originate from developing
countries(Mandras, Mehta, \& Vaidya, 2020). There are numerous
subcategories of PAH, and similar pathological changes occur in almost
all of them, including the destruction of endothelial cells (ECs) and
proliferation of pulmonary artery mesenchymal stem cells (PASMCs). Over
time, the affected blood vessels become stiffer and thicker, which
finally leads to PAH. Until now, there has been no existing radical
therapy for PAH(Schermuly et al., 2011). Current treatment options
include targeted therapies, such as endothelial receptor antagonist,
guanylate cyclase antagonist, type 5 phosphodiesterase inhibitor, and
prostaglandin drugs. The purpose of these drugs is only to block PAH
pathways and delay the progression of disease, but these treatments do
not significantly reduce mortality, which still remains at approximately
50\% at five years(Schermuly et al., 2011). In this review, we attempt
to provide a stem cell therapy that may potentially reverse the
occurrence of PAH and effectively reduce its mortality. To analyze the
unique advantages and potential challenges, we will discuss five aspects
of therapy: (i) classification, (ii) mechanism, (iii) correlation, (iv)
preclinical research, and (v) clinical research.

According to the process of differentiation, there are 5 different types
of stem cells: (i) totipotent, (ii) pluripotent, (iii) multipotent, (iv)
oligopotent, and (v) unipotent precursor cells(Toshner et al., 2009)
(Figure 1). Totipotent stem cells have the strongest replication and
differentiation capacity, and can differentiate to three germ layers and
the trophectoderm (TE, such as the placenta). The most common example of
totipotent stem cells is a zygote. Thus, totipotent stem cells are
capable of forming every organ, including an entity under the correct
support environment. Then, the inner cell mass (ICM), a part of the
embryoblast, finally becomes pluripotent stem cells after a session of
replication and differentiation(Mitalipov \& Wolf, 2009). Pluripotent
stem cells also are able to differentiate to three germ layers, but they
cannot differentiate to the trophectoderm because the source of
pluripotent stem cells is the inner cell mass but not a trophoblast.
Therefore, totipotent stem cells can form an entire entity, while
pluripotent stem cells can only form mature cells derived from three
germ layers. Of course, there are well-known examples of pluripotent
stem cells, such as embryonic stem cells (ESCs) and induced-pluripotent
stem cells (iPSCs). After differentiation, pluripotent stem cells become
next stage, multipotent stem cells(Ulloa-Montoya, Verfaillie, \& Hu,
2005). Multipotent stem cells still possess a strong capacity for
replication and differentiation, and these cells can differentiate to a
specific germ layer. Therefore, different types of multipotent stem
cells have specific names depending on their differentiation
orientation, such as hematopoietic stem cells, mesenchymal stem cells,
neural stem cells, and skin stem cells.

Along with the process of differentiation, multipotent stem cells
gradually lose the capacity to differentiate to a germ layer, and they
finally become oligopotent stem cells. Oligopotent stem cells have the
capacity to differentiate to a specific category of tissue, but they
cannot become other type of cells. For example, myeloid cells can only
become granulocytes, and not red blood cells. Unipotent stem cells have
the weakest capacity of replication and differentiation. Although this
type of cell can only differentiate to specific cells, they possess the
ability to self-renewal, which distinguishes them from non-stem cells
(e.g., progenitor cells)(M. Xu, He, Zhang, Xu, \& Wang, 2019). Some
studies found that a small proportion of multipotent stem cells and
unipotent stem cells could revert to a trophectoderm or pluripotent stem
cells, respectively, and the reason for this phenomenon may be
attributed to the redifferentiation process. This discovery may provide
a novel method that can be used to broaden the applications of stem cell
therapy(Y. Yang et al., 2018).

\textbf{2. Characterization and Classification}

\textbf{2.1 Endothelial progenitor cells (EPCs)}

The controversy surrounding EPC definition are beginning from the first
observations of blood vessel development in 1917, but after a long
period of discussion, the precise definition of EPC are still
unclear(Ferkowicz \& Yoder, 2005). The most accessed definition of EPC
is that progenitor cells are a heterogeneous population which includes
different origins and several residing sites at different maturity
stages(Yang, Pan, Wang, Qiu, \& Mao, 2018). Due to the different
features of cells, it is difficult to produce a worldwide accepted
characterization of EPCs(Richardson \& Yoder, 2011). Additionally, due
to the different characterizations of EPCs, some contrary results have
emerged(Harper et al., 2019; Toshner et al., 2009; Zhou et al., 2013).
Balistreri et al. argued that EPCs are a type of stem cell(Bianconi et
al., 2018; Prokopi \& Mayr, 2011). In their opinion, progenitor cells
are an intermediate stage between multipotent stem cells and mature
cells, and both stem cells and progenitor cells have the ability to
replicate and differentiate to mature cells, and even have the same
biological markers(Brown \& McGuire, 2012). EPCs can adhere to matrix
molecules such as fibronectin and demonstrate dual positivity to
acetylated low-density lipoprotein (acLDL) and \emph{Ulex
europaeus}agglutinin I (UEA-1) lectin(Yang, Pan, Zhao, \& Wang, 2013).
These types of cells commonly have some common positive protein such as
CD34+ and CD133+ (which are two unique markers of hematopoietic stem
cells), vascular endothelial growth factor receptor-2 (VEGFR2+, also
called kinase insert domain receptor (KDR)/fetal liver kinase-1 (Flk-1),
which is an important regulator of development of ECs and vasculature),
and von Willebrand factor+ (vWF+), CD31+, CD144+, CD146+, and
endothelial nitric oxide synthase+(eNOS+).

EPCs in different classifications are characterized by different
abilities and affinities. According to the number of culture days after
monocytes are extracted from blood(Hansmann et al., 2011), EPCs can be
divided into early-outgrowth EPCs and late-outgrowth EPCs(Pelosi,
Castelli, \& Testa, 2014; Prokopi \& Mayr, 2011). Early-outgrowth EPCs,
also called circulatory angiogenic cells (CACs)(Basile \& Yoder, 2014;
Prater, Case, Ingram, \& Yoder, 2007), are a spindle-shaped cell that
emerges after culturing for 4-7 days(Murohara, 2010). Its name indicates
that this type of EPC possesses little differentiation capacity, and
thus, these cells cannot become mature cells(Paneni, Costantino,
Kr\selectlanguage{ngerman}änkel, Cosentino, \& Lüscher, 2016). However, early-outgrowth EPCs
have a significant capacity to release several cell growth factors and
cytokines such as vascular endothelial growth factor (VEGF), hepatocyte
growth factor (HGF), granulocyte colony stimulating factor (G-CSF),
granulocyte/macrophage colony-stimulating factor (GM-CSF), and
interleukin (IL)-8(Guber, Ebrahimian, Heidari, Eliopoulos, \& Lehoux,
2018; J. X. Yang et al., 2018). Due to their unique biological
behaviors, early-outgrowth EPCs exert their function mainly by secreting
growth factors and cytokines to support the growth of adherent cells and
surrounding late-outgrowth EPCs. Except for custom EPC markers,
early-outgrowth EPCs also express CD45 and CD14(S. J. Zhang et al.,
2006).

Other cell groups emerged after 14-21 days of culture, and these
cobblestone-shaped cells are named late-outgrowth EPCs, and also are
called endothelial outgrowth cells (EOCs)(S. Liu et al., 2018), although
they are different from early-outgrowth EPCs. The late-outgrowth EPCs
display a significant capacity to replicate and differentiate to mature
ECs. Compared with typical EPCs, late-outgrowth EPCs do not express
hematopoietic stem cells markers, but instead, express vascular
endothelial-cadherin (VE-cadherin) and CD146(Minami et al., 2015).

Given their biological properties, some researchers recognize that
early-outgrowth EPCs and late-outgrowth EPCs are not single types of
cells in different stages, but they may differentiate from different
cells(Medina et al., 2010). There also exist a small proportion of EPCs
that remain in the microcirculation of lung vessels before occurrence of
injury(Schniedermann et al., 2010). Therefore, we called this type of
EPC resident EPCs (in contrast to circulating EPCs). Resident EPCs
display a significant replication and differentiation capacity,
suggesting that lung blood and lymphatic ECs may be derived from these
cells. However, based on our existing research results, we cannot
clearly distinguish this cell type, and therefore, further study is
required to discern the nature between resident EPCs and circulating
EPCs.

\textbf{2.2 Mesenchymal stem cells (MSCs)}

MSCs, also known as mesenchymal stromal cells, are multipotent stem
cells that can differentiate into numerous cells types such as
osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes
(muscle cells), and adipocytes (fat cells)(Ong, Ankrum, Dastidar, Levy,
\& Karp, 2014; Tonk, Witzler, Schulze, \& Tobia Sc H, 2020). The
morphology of MSCs is also characteristic, as MSCs have a small cell
body with long and thin processes that are widely dispersed and
populated in the adjacent extracellular matrix. In label-free live cell
imaging, some organelles can be seen, and MSCs are clearly defined due
to these distinct morphological features(Richmond, 1992). According to
the International Society for Cellular Therapy (ISCT), MSCs are
characterized by the following criteria: (1) expression of a specific
set of clusters of differentiation CD markers (CD73, CD90, and CD105),
(2) lack of expression of hematopoietic lineage CD markers {[}CD45,
CD34, CD14 or CD11b, CD79a or CD19, human leukocyte antigen-antigen D
related (HLA-DR){]}, (3) plastic adherence under standard culture
conditions, (4) the ability to differentiate into osteoblasts,
adipocytes, and chondroblasts \emph{in vitro} (Fukumitsu \& Suzuki,
2019).

Due to the clear definition, it is much easier to classify MSCs than
EPCs. The most acknowledged classification is cell source, and the most
common extraction sources are umbilical cord blood, amniotic fluid,
adipose, and bone marrow, and different sources of MSCs possess
different biological properties (Figure 2). The abundance and healing
capacity of stem cells from umbilical cord blood are much higher as
compared to amniotic fluid, and adipose and bone marrow stem cells.
However, the replication and differentiation capacity not only correlate
with the cell source, but also with the age of donors. Research shows
that the doubling time and activity generation significantly decrease
when age increases(Fraser, Wulur, Alfonso, \& Hedrick, 2006; Pittenger
et al., 1999).

The immunogenicity is also different between different cell sources.
MSCs from bone marrow possess the highest immunogenicity because they
have a higher expression level of HLA-DR under an inflammatory
microenvironment (such as a high concentration of tumor necrosis
factor-\selectlanguage{greek}α \selectlanguage{english}(TNF-\selectlanguage{greek}α\selectlanguage{english}) and interferon gamma (IFN-\selectlanguage{greek}γ\selectlanguage{english})), which will cause the
immune cells to identify them and more rapidly eliminate them. The
differentiation tendency is also different, as MSCs from umbilical cord
blood tend to secrete additional hematopoietic factors such as G-CSF,
GM-CSF, and HGF. Therefore, this type of MSC is more well-equipped to
support the blood system. Additionally, MSCs from bone marrow can
secrete a greater amount of VEGF than MSCs from umbilical cord blood,
which enables MSCs from bone marrow to more easily form
neovessels(Baksh, Yao, \& Tuan, 2007; Hass, Kasper, B\selectlanguage{ngerman}öhm, \& Jacobs,
2011; Peng et al., 2008; Y.-Y. Shi, R. P. Nacamuli, A. Salim, \& M. T.
Longaker, 2005; Van Harmelen, Röhrig, \& Hauner, 2004; Weiss et al.,
2006).

\textbf{2.2 Induced pluripotent stem cells (IPSCs)}

IPSCs are a type of pluripotent stem cell that can be directly generated
from somatic cells. Due to this characterization, there is great
interest in IPSC technology worldwide. IPSC technology was pioneered by
Dr. Shinya Yamanaka in 2006, when he introduced four specific genes
named Myc, octamer-binding transcription factor 4 (Oct3/4), sex
determining region Y-box 2 (Sox2), and kruppel like factor 4 (Klf4)
(which were also named Yamanaka factors), and then, encoding
transcription factors could convert somatic cells into pluripotent stem
cells. Yamanaka used this technology, and was awarded the 2012 Nobel
Prize along with Sir John Gurdon ``for the discovery that mature cells
can be reprogrammed to become pluripotent(Takahashi \& Yamanaka, 2006).

\textbf{3. Preclinical research on stem cells in PAH}

\textbf{3.1 EPCs}

\textbf{3.11 PAH and EPCs}

The usual hypothesis is that a low level of EPCs is one of the
conditions for the occurrence of PAH. In research regarding congenital
heart disease (CHD) that caused PAH in childhood, severe PAH patients
(mean pulmonary arterial pressure \textgreater{} 25 mmHg) show a
significantly lower EPC level as compared to non-PAH patients. This
phenomenon shows that low level of EPCs is strongly correlated with PAH.
However, this relationship was not apparent for patients with mild PAH,
indicating that a decreased level of EPC is not the only pathogenesis,
or the EPC level will not be significantly decreased in the early stage
of PAH(H. X. Sun et al., 2019). The same result was also obtained for
adult patients, and in a comparison of COPD and COPD-PAH patients, the
latter group showed a significantly lower EPC level as compared to COPD
patients(P. Liu et al., 2016). A different conclusion was reached by a
group of English scientists, who found that the level of EPCs was
increased in idiopathic pulmonary arterial hypertension (iPAH) patients
with bone morphogenetic protein type II receptor (BMPR2) mutation (which
is a classical mutation that results in the development of iPAH).

In order to explain this aberration, a comparison was made between the
EPC screening conditions in different studies (Table 1). We found that
almost all scientists use different testing conditions, and the
different markers may correspond to different cell groups and different
cell functions, finally leading to the chaos of conclusions(Toshner et
al., 2009). These different definitions of EPCs cause academic
disruption that increases the difficulty and cost of discussions and
experiments, and eventually leads to the standstill of progress. Despite
the existence of contrary opinions, there is a consensus by most
scientists that the low level of EPCs is part of an indispensable
process that results in the development of PAH. They suggest that in the
initial stage of PAH, high levels of cycling EPCs are able to repair the
loss of vessels. However, with the progression of disease, the
continuous damage exceeds the compensatory ability of EPCs, which
finally leads to the reduction of peripheral EPCs and additional
destruction of vessel structure. Ultimately, this process causes stiffer
and narrower vessels and a higher pulmonary arterial pressure.

Under this vicious cycle, the symptoms of PAH become increasingly severe
and finally lead to death(Toshner et al., 2009). EPCs exist in numerous
ways to prevent the development and reverse existing PAH, and mainly
include direct incorporation to sites of impaired vessels for repair,
playing supportive roles in cellular repair, inhibiting the transfer of
ECs, and participating in immunosuppression functions and secretion
functions such as secretome, exosome and extracellular vehicles
(EVs)(Bayraktutan, 2019; Bianconi et al., 2018; Wei et al., 2013).

\textbf{3.12 Preclinical research on EPCs in PAH}

Because EPCs have numerous capacities such as proliferation, migration,
and adhesion to protect the normal structure of ECs and PASMCs,
scientists use EPCs to attenuate and reverse PAH. Zhao et al. injected
fluorescently labeled EPCs into monocrotaline (MCT)-induced PAH mice,
the EPCs integrated into the distal pulmonary artery endothelium and
limited the progression of PAH through differentiation to mature ECs and
alleviation of neointima formation(Yang et al., 2013). Zhao et al. also
detected EPC-derived proangiogenic growth factors (such as IL-8 and
adrenomedullin) in the adjacent area of EPCs through autocrine and
paracrine methodology. Zheng et al. found that EVs of EPCs transport
mRNA to ECs, and express a series of proteins such as chemokines,
pathway proteins, and growth factors to enhance EC proliferation and
migration and decrease angiogenesis(Deregibus et al., 2007; Ingram et
al., 2004; X. Li et al., 2016). Zhao et al. used EPCs to treat
monocrotaline (MCT)-induced PAH mice at two different time points to
explore the effect of EPCs on different disease stages. The results
seemed inspiring, as compared with the MCT group, the hemodynamic
improvement in both groups was significant, but both treatment groups
still had a higher mean pulmonary arterial pressure (mPAP) than the
control group, indicating that EPCs can prevent but cannot reverse the
occurrence of PAH. Zhao et al. also investigated the microstructure of
the pulmonary artery under EPC therapy. They stained the pulmonary
artery with fluorescent microspheres and alpha-smooth muscle actin
(\selectlanguage{greek}α-\selectlanguage{english}sma) to visualize the structure of PASMCs and microvasculature
perfusion. The results showed that the 21-day and 35-day groups
dramatically increased their microvascular perfusion and
microvasculature after EPC treatment(Y. D. Zhao et al., 2005).

As a nonoral therapy, use frequency is also an important indicator of
feasibility. Therefore, Harper et al. and Zhou et al. investigated the
stay time and stay location after EPC transplantation. Harper et al.
selected cells expressing CD34, CD306, CD146, and CD45 by
fluorescence-activated cell sorting (FACS) and transfected adenoviral
vectors carrying the luciferase and GFP reporter gene. The
immunofluorescence results showed that at 1 h and 7 h after EPC
transplantation, most of the luminescence was located in the chest
region, and there was little or no luminescence in other areas, the
luciferase results were same. Compared with the control group, the
concentration of EPCs in the lung was two times higher than that in the
spleen. This shows that EPCs tend to aggregate in damaged endothelial
tissues, but rarely aggregate in integrated tissues. According to the
above evidence, EPC therapy seems to be a targeting therapy that has
little impact on other organs, at least in concentration
relationships(Harper et al., 2019; Zhou et al., 2013). However, the
experiment by Zhou et al. produced some opposite results. He found that
the retention rate of EPCs was still nearly 50\% 25 days after
transplantation(Zhou et al., 2013). These contrary results were caused
by different screening conditions during FACS.

In order to improve the effect of EPC therapy, scientists use gene
editing technology. Wei et al. used Ad.CMV-human endothelialNO synthase
enzymes (Ad.CMV-heNOS), Ad.CMV, or Ad.CMV-enhanced green fluorescent
protein (Ad.CMV-EGFP) to infect EPCs for 72 h. Two weeks after the
injection, the systolic arterial pressure (ASP) of mice did not
significantly change, but the systolic pulmonary artery pressure (sPAP)
significantly decreased in both the simple EPC group and the heNOS-EPC
group. Furthermore, the heNOS-EPC group was significantly lower than the
vector-EPC-treated group and the normal EPC-treated group. The histology
results also showed the same trend, with a significant reduction in the
number of muscular pulmonary arteries and thickness of the muscular
coat(Wei et al., 2013).

Cao et al. selected the human hypoxia inducible factor-1 alpha (hHIF-1\selectlanguage{greek}α\selectlanguage{english})
gene and transfected it into EPCs. Compared with the EPC group and blank
group, hHIF-1-EPCs significantly reversed the vascular remodeling, and
decreased the sPAP, mPAP, and right ventricular/left ventricular +
septum (RV/LV+S). Xu et al. chose to disturb the metabolic process of
the pulmonary artery to control the progression of PAH. They used
lentiviral vectors to inhibit the expression of E2F transcription factor
1 (E2F1) and subsequently increase oxidative metabolism, endothelial
differentiation, vascular repair, and decrease the pyruvate
dehydrogenase kinase 4/2 (PDK4/2) expression. The metabolic level was
measured by the oxygen consumption rate (OCR), extracellular
acidification rate (ECAR), and lactate level. The results showed that
E2F1-/- mice had a greater OCR, a lower ECAR, and a lower level of
lactate (which represents a lower anaerobic respiration level),
indicating that E2F1-/-EPC enhanced vascular growth, reduced infarct
size, and improved vascular function through increasing the oxygen
utilization rate of pulmonary ECs(Cao et al., 2015; S. Xu et al., 2018).

Dysfunctions of the prostacyclin (PGI) pathway are also an important
factor in the occurrence of PAH. Therefore, Zhou et al. tried to
engineer the cyclooxygenase-prostacyclin (COX-PGI) pathway to improve
the effect of EPCs. The engineered EPCs significantly attenuated the
RVSP increase, RV hypertrophy, and intimal and medial smooth muscle
layer cell proliferation, and enhanced adventitial pulmonary vessel wall
apoptosis(Zhou et al., 2013).

\textbf{3.2 MSCs}

\textbf{3.21 PAH and MSCs}

MSCs also have a significant ability to prevent the occurrence of PAH
and reverse existing PAH in a manner similar to that of EPCs. Liu et al.
found that MSCs can promote the repair of ECs through increasing the
proliferation, migration, and tube formation of ECs to inhibit PAH.
Inflammatory regulation also plays a role that cannot easily be
overlooked, under the treatment of MSCs, the level of anti-inflammatory
cytokines (such as TGF-\selectlanguage{greek}β, \selectlanguage{english}IL-1, and prostaglandin E2) were increased(A.
Liu et al., 2020; J. Liu et al., 2021), the level of pro-inflammatory
cytokines (such as IL-1\selectlanguage{greek}β, \selectlanguage{english}IFN-\selectlanguage{greek}γ, \selectlanguage{english}and TNF-\selectlanguage{greek}α\selectlanguage{english}) and angiogenic factors (such
as VEGF, vWF, and fibroblast growth factor) were significantly
reduced(Bull, Clark, McFann, \& Moss, 2010), what's more, MSCs can
attenuate the proliferation of dendritic cells (DCs) and secretion of
IL-10 which inhibits the expression of CD80 and CD83 (which are
co-stimulation factors of DC), and inhibiting the maturation of DCs(S.
Zhang et al., 2018).

What's more, the effect of exosomes and secretomes has also been
experimentally verified, both murine MSC extracellular vesicles
(mMSC-EXs) and human MSC extracellular vesicles (hMSC-EXs) have a
significant healing effect on mouse PAH models (Figure 3)(Jason M.
Aliotta et al., 2016; Bian et al., 2014; Hu et al., 2018; Lopatina et
al., 2014).

\textbf{3.22 Preclinical treatment with MSCs in PAH}

The research about MSC therapy in PAH is much earlier than EPC therapy,
and the effect of MSC therapy is also more recognized. Huang et al.
showed that after MSC transplantation, sugen-hypoxia induced-PH (Su-Hx
PH) rats and chronic hypoxia-induced pulmonary hypertension (CHPH) rats
exhibited a significant decrease in right ventricle pressure and degree
of pulmonary artery remodeling. Masson's trichrome staining results
showed that MSCs ameliorated the collagen deposition around the
pulmonary arterial vasculature. MSCs also attenuated the process of
endothelial-to-mesenchymal transition (EndMT) by reducing the expression
of HIF-2\selectlanguage{greek}α\selectlanguage{english}(J. Huang et al., 2020). Furthermore, Huang et al. also
investigated the secretory function of MSCs by injecting MSC conditional
medium (MSC-CM) into mice, and they obtained the same trend as that
observed with cell suspension.

These results showed that the both control group and experimental groups
exhibited a high level of HIF-2\selectlanguage{greek}α \selectlanguage{english}under hypoxic conditions. However, the
group that received MSC-CM treatment exhibited a faster disappearance
rate of HIF-2\selectlanguage{greek}α, \selectlanguage{english}indicating that MSC-CM inhibited HIF-2\selectlanguage{greek}α \selectlanguage{english}by promoting its
degradation(J. Huang et al., 2020).

Rathinasabapathy et al. found that adipose source MSCs (ASCs) and their
conditional medium can modulate numerous types of cytokines, including
significantly downregulating pro-inflammatory cytokines such as TNF\selectlanguage{greek}α,
\selectlanguage{english}IL-1, and IL-6, markers of immune defense system such as toll-like
receptor 4 (TLR-4), cytokine-inducible NOS (iNOS), and markers of tissue
remodeling such as TGF-\selectlanguage{greek}β, \selectlanguage{english}and upregulating the markers of
anti-inflammatory cytokines such as IL-10(Rathinasabapathy et al.,
2016). In the past decade, an increasing number of scientists has
concentrated their attention on the exosome of MSCs. Without exception,
the exosome of MSCs was also effective, as some scientists found that
the expression levels of Wnt5a, Wnt11, BMPR2, BMP4, and BMP9 increased,
but \selectlanguage{greek}β-\selectlanguage{english}catenin, cyclin D1, and TGF-\selectlanguage{greek}β\selectlanguage{english}1 decreased in the MSC exosome group
in vivo and in vitro. Considering that the immunogenicity of exosomes is
lower than that of a cell suspension, if we have an efficient method to
obtain sufficient exosomes, then these exosomes may constitute a more
effective treatment (Table 2).

Chen et al. transfected MSCs with the eNOS and F92A-Cav1 genes using
lentivirus vector to verify the feasibility of gene editing technology
in MSCs and increase the effect of MSCs. The results showed that the
serum NO concentration significantly increased in eNOS-MSCs, and
eNOS/F92A-Cav1-MSCs inhibited proliferation of PASMCs and improved
pulmonary hemodynamics, vascular remodeling, and short-term survival(H.
Chen et al., 2017). Cheng et al. used adenovirus to transfect MSCs with
the lethal-7a (let-7a) microRNA, so that the let-7a-MSCs would
overexpress let-7a microRNA, and the results showed that let-7a-MSCs
ameliorated MCT-induced ventricular impairment, attenuated pulmonary
vascular remodeling, and regulated PASMC proliferation and apoptosis
resistance(Cheng, Wang, Li, \& He, 2017).

\textbf{3.3 IPSCs}

\textbf{3.31 Preclinical treatment with IPSCs in PAH}

As an rising technology, rely on IPSCs to treat diseases has been
applied in many fields including cardiovascular disease,
neurodegenerative disease, it also includes respiratory diseases. Huang
et al. use IPSCs and IPSCs-CM to treat MCT-induced PAH, the results show
that IPSC-based therapy led to decreased accumulation of inflammatory
cells and down-regulated the expression of pro-inflammatory factors
through inhibit the phosphorylation of NF-\selectlanguage{greek}κ\selectlanguage{english}B pathway(W. C. Huang et al.,
2016).

\textbf{4. Clinical application of stem cells in PAH}

\textbf{4.1 EPCs}

Until now, the clinical application of EPCs in PAH has been rare (Table
3). The search results from clinicaltrials show that only China and
Canada have achieved EPC therapy trials using human patients. Of the 31
idiopathic PAH patients in the Chinese trial, 16 patients were randomly
selected to receive conventional therapy, and 15 patients were randomly
selected to receive EPC infusion plus conventional therapy. This trial
lasted for 12 weeks, and the frequency and degree of adverse events were
similar between the 2 groups (\emph{p} \textgreater{}0.05)(X. X. Wang et
al., 2007). However, the cell infusion group exhibited a significant
improvement in mean distance walked in 6 minutes, mPAP, pulmonary
vascular resistance, and cardiac output. The Canadian trial was more
radical because they used gene-edited EPCs in patients who were
refractory to conventional therapy. They injected seven patients with
eNOS-EPCs, but the number of patients was far less than that in the
Chinese trial, and there were five female subjects but only two male
subjects. Similar to the Chinese trial, the infusion of EPCs was well
tolerated in the cell infusion group, and there was a significant
increase in the mean distance walked in 6 minutes over all 6 months.
However, it is worth noting that some improvements (such as
hemodynamics) disappeared after 3 months, which may be due to the short
duration of EPCs(Granton et al., 2015).

\textbf{4.2 MSCs}

Until now, the only legal clinical stem-cell therapy was hematopoietic
stem-cell therapy for childhood leukemia. Other therapies remain
controversial because they are often related to abortion politics and
human cloning. However, the research field of stem-cell therapy is
constantly expanding, and scientists now have applied stem cells in
neurodegeneration, brain and spinal cord injury, frailty syndrome,
pancreatic beta cells, orthopedics, and other uses(Gazdic et al., 2018;
Golpanian et al., 2017; R. Li et al., 2018; Lyon, 2018; Memon \&
Abdelalim, 2020). The significant difference between EPCs and MSCs is
that a lower immunogenicity is associated with MSCs. However, if low
immunogenicity leads to lengthy transplantation time and excessive
allogeneic cells in the circulation of patients, this may lead to
graft-versus-host disease (GVHD), which is the most severe side effect
of stem cell therapy(Malard \& Mohty, 2014).

Ethical issues continue to cause problems with allografts because
embryonic stem cells are derived from human embryos, but this process
will kill the embryo. A key issue is the voluntary actions of donors,
and therefore, the choice of donation must be later than the choice of
abortion, so as to avoid involuntary activities caused by monetary
temptation or other factors. In addition to ethical issues, there are
also many criticisms of the experimental procedures. Some critics report
that only five basic trials seem to be used in 48 reports, and many
trials contradict each other. Therefore, research into clinical stem
cell therapy requires further development and stricter standards to
limit disordered behavior and prevent damage to the reputation of
scientists and the field of stem cell therapy(Heo, Choi, Kim, \& Kim,
2016). He identity of patients after allogeneic stem cell
transplantation is another inevitable problem. Because allogeneic stem
cells can differentiate into allogeneic mature cells, the identity of
patients still needs to be further discussed and confirmed. It is
advantageous that the new technology of inducing pluripotent stem cells
avoids this ethical tissue, and another benefit is that it provides even
more convenient access as compared to autologous stem cells(Y. Y. Shi,
R. P. Nacamuli, A. Salim, \& M. T. Longaker, 2005).

\textbf{4.3 IPSCs}

The appearance of IPSCs has profound implications for the source of
pluripotent stem cells. Because the access of embryonic stem cells is
controversial, IPSC technology sidesteps a majority of the ethical
issues, which results in the acceptability of stem-cell therapy for wide
application. However, there is still a lack of understanding regarding
IPSCs, which are currently not being used for clinical therapy. Current
clinical application of IPSCs is restricted for cell models of diseases,
which remain difficult for scientists to simulate in vitro. Because
patients' somatic cells can revert back to pluripotent stem cells after
utilization of IPSC technology, then under the current steering, normal
somatic cells can become model cells. Considering this characterization,
IPSC technology is an ideal method for acquiring model cells through
patients' somatic cells because it does not cause obvious damage to
patients. Sa et al. compared IPSC-derived ECs and native pulmonary ECs
of iPAH patients in order to investigate the feasibility of IPSC-derived
cells. The results showed that two types of cells manifest a similar
phenotype. This result indicates that enormous progress has been made,
because whether sugen, hypoxia, or MCT-induced PAH has a certain gap
with iPAH, the easier method to derive human-source disease model cells,
which is a huge leap for exploring the real mechanisms of iPAH(Sa et
al., 2017).

In the past 2 years, IPSC therapy trials in patients have also been
established. However, all IPSC clinical therapy trials are still in the
recruiting stage. Only after a session of completed research will we be
finally able to evaluate the feasibility and effectiveness of IPSC
therapy and then consider whether IPSC therapy can finally become a
feasible treatment for human diseases.

\textbf{5. Challenge and future prospects}

Both MSC therapy and EPC therapy are promising due to their outstanding
effectiveness and low toxicity, and the effects of MSC therapy and EPC
therapy also have been verified in many diseases thus far. However,
because of our limited understanding of cell differentiation regulation,
we poorly predict the further development of transplanted MSCs and EPCs.
Except for ethical issues, challenges mainly include the following three
aspects (Luo et al., 2013).(1) Low abundance: Human stem cells are
derived from human tissue such as bone marrow, adipose, amniotic fluid,
and umbilical cord blood, and therefore, due to the sparse volume of
tissue, obtaining vast numbers of stem cells will become an
insurmountable hurdle. However, the emergence of IPSC technology may
solve this problem. There exist many methods to induce somatic cells,
including virus, vector, mRNA, protein, small molecules, and
miRNA(Ichida et al., 2009; Moradi, Braun, \& Baharvand, 2018; Moradi et
al., 2017; Zhu et al., 2010). Unfortunately, the most efficient method
is accompanied by the highest danger. Therefore, further study is
necessary to obtain a method that will balance safety and
efficiency(Okita, Nakagawa, Hyenjong, Ichisaka, \& Yamanaka, 2008;
Stadtfeld, Nagaya, Utikal, Weir, \& Hochedlinger, 2008; Woltjen et al.,
2009). (2) Genomic insertion and incomplete reprogramming: Gene editing
technology and inducing pluripotent stem cell technology require
carriers to transfect transcription factors, while under some rare
situations, exogenous cDNA can be inserted into the host's chromosomal
DNA. However, due to undetectable mutations and unknown genesis
positions, nobody knows what will happen if genomic insertion occurs or
if incomplete reprogrammed stem cells replicate and differentiate in a
patients' body(Selvaraj, Plane, Williams, \& Deng, 2010). (3)
Tumorigenicity: all stem cells probably develop to tumor cells after
replication and differentiation for a long period of time. This
phenomenon has been verified by many studies, because all stem cell
transplantations finally develop to a tumor. Additionally, the process
of inducing pluripotent stem cell technology also increases the
tumorigenicity of pluripotent stem cells, because the transcription
factor Myc is a protooncogene that will lead to the occurrence of
tumors. Fortunately, Yamanaka reported that a new technology can create
IPSCs without Myc(Aguilar-Gallardo, Crist\selectlanguage{ngerman}óbal, Simón, \& Carlos, 2013),
and although its efficiency is much lower, this provides us with a
satisfactory idea for safety technology(Marión et al., 2009).

The future of stem cell therapy is promising. In the past 2 decades,
stem cell therapy has been applied to numerous fields, including
interstitial pulmonary fibrosis, limbal stem cell deficiency,
progressive multiple sclerosis, diabetes, myocardial infarction, and
neurodegenerative disease. Different from other conventional drug
therapies for pathogenesis, stem cell therapy has obvious advantages
because it can directly involve in cell regeneration. Therefore, stem
cells provide a new therapy that conventional drug therapy cannot
achieve.

A large number of animal studies and clinical trials show that
significant improvement results from combined therapy as compared with
traditional drug therapy. However, stem cell therapy is not a mature
therapy because we know little about its potential mechanism. Therefore,
in the next stage of research, we should first design new experiments to
explore the detailed mechanisms of stem cell therapy, and second, we
should summarize clinical experiences to provide a suitable therapy
course. Last but not least, we should discuss the ethical issues
regarding allotransplantation. If we can obtain insight into the
specific mechanism of stem cell therapy and achieve a feasible consensus
regarding allotransplantation, then the applications for stem cell
therapy will greatly expand.

\textbf{Acknowledgements}

Not applicable.

\textbf{Authors' contributions}

ZRX and XMY collected literatures, prepared figures and tables, and
drafted the manuscript. WXH edited the manuscript. YLH, WJ and HXY
conceived the idea and reviewed the manuscript. All authors read and
approved the final manuscript.

\textbf{Funding}

This work was supported by the National Natural Science Foundation of
China (82170061).

\textbf{Ethics approval and consent to participate}

Not applicable.

\textbf{Competing interests}

The authors declare that they have no competing interests.

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doi:10.1016/j.stem.2010.11.015\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1. Stem cell differentiation process.}

This is the differentiation tree of stem cells from zygote to progenitor
cell. Progenitor cells are unipotent stem cells that have the weakest
capacity for differentiation and replication. In the mesoderm,
endothelial progenitor cells, neural progenitor cells, pancreatic
progenitor cells, and cardiac progenitor cells are involved. A
multipotent stem cell is a monibus term; in the mesoderm, mesenchymal
stem cells, hematopoietic stem cells, neural stem cells, and skin stem
cells are involved. iPSCs are manufactured stem cells, and this type of
pluripotent stem cell possesses functions similar to those of
traditional pluripotent stem cells.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2. Mechanism of stem cell therapy.}

Stem cells can inhibit and reverse vessel pathological changes through
numerous methods. Stem cells can inhibit the proliferation of SMCs and
promote the differentiation of ECs. Of course, the secretory function
also plays a critical role in efficacy and outcomes. Stem cells inhibit
the secretion of pro-inflammatory factors and promote the secretion of
anti-inflammatory factors. Stem cells also secrete microvesicles and
exosomes, and under the comprehensive effect, diseased blood vessel
revert to normal blood vessels.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3. Mechanism of stem cell therapy.}

Stem cells can inhibit and reverse vessel pathological changes through
numerous methods. Stem cells can inhibit the proliferation of SMCs and
promote the differentiation of ECs. Of course, the secretory function
also plays a critical role in efficacy and outcomes. Stem cells inhibit
the secretion of pro-inflammatory factors and promote the secretion of
anti-inflammatory factors. Stem cells also secrete microvesicles and
exosomes, and under the comprehensive effect, diseased blood vessel
revert to normal blood vessels.

\textbf{Table 1.} Summary of recent literature regarding EPC
immunological markers\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Flow cytometry makers}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Source}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Target}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Conclusion}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Reference}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD133 (+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Correlation between EPC and PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
The number of EPC decreased in PAH patients\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(H. X. Sun et al., 2019)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD34(+), CD146(+), CD45(+), CD309(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Bone marrow\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Gene editing EPC therapy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
BMPR2-expressing EPC alleviate PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Harper et al., 2019)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD34(+), CD133(+), CD309(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Drug effect to EPC and PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Riociguat increase the number of EPC to protect CTEPH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Yamamoto et al., 2020)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD34(+) CD31(+), CD144(+), VEGFR-2(+), eNOS (+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Regulatory Pathway of EPC\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Stimulation of NOX2, NOX4 and VPO1 induce EPC's apoptosis and
dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(E. L. Wang et al., 2019)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
sca-1(+), CD117(+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Bone marrow\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
extracellular vesicles' different effect under different
microenvironment\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
MSC-EV reduce the number of EPC in increase the expression of EPC genes
in MCT-PH mice\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
(J. M. Aliotta et al., 2017)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD31(+), VEGFR-2(+), CD144(+), CD34(+), CD14(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Factors influence to distribution of EPC\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
chemokine and cell Adhesion Molecules attract EPC to lung\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Y. Liu et al., 2020)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD34(+), CD133(+), CD31(+), CD45(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Bone marrow\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Drug effect to EPC and PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
pinocembrin has a supportive effect to EPC in MCT-PH rats\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Ahmed, Rizk, \& El-Maraghy, 2017)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD45(+), CD34(+), CD133(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Bone marrow\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Correlation between EPC and PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
COPD patients have a lower level of EPCs\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Pizarro et al., 2014)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD34(+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Peripheral blood and lung tissue\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Correlation between EPC and PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
COPD patients have a lower level of EPCs, but COPD-PH patients have a
higher level of EPCs\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Y. Yang et al., 2018)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ZsGreen (+), CD117(+), CD45(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Bone marrow\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Correlation between EPC and EHT\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Sugen-hypoxia mice's EPCs unable to transfer PH pathology to recipient
mice\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Liang et al., 2017)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD34(+), CD45(+), CD14(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Function of EPCs\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
different markers EPCs have different function\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Foris et al., 2016)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD133 (+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Correlation between EPC and PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
EPC number and vasculogenesis increase in 48h, but significantly reduce
after 6 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Xia et al., 2009)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD31(+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Bone marrow\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Gene editing EPC therapy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
E2F1 deficiency EPCs improve the effect of EPC\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(S. Xu et al., 2018)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD34(+), CD14(+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Correlation between EPC and PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
number of EPCs is negatively correlated with the PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(P. Liu et al., 2016)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD45(+), CD34(+), CD133(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Correlation between EPC and PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
number of EPCs is significantly reduced in PAH patients\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Garc\selectlanguage{ngerman}ía-Lucio et al., 2017)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
CD34(+), AC133(+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Correlation between EPC and PAH\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
number of EPCs is significantly reduced in PAH patients\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
(Diller et al., 2008)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD34(+), CD133(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Function of EPC therapy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
EPCs can reduce the symptoms of PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Q. Zhao et al., 2007)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD31(+), VEGFR-2(+), vWF (+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Bone marrow\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Function of EPC therapy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
EPCs can alleviate PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(C. K. Sun et al., 2012)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
CD34(+), CD133(+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Bone marrow\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Function of EPC therapy\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
HIF1-EPCs can alleviate PAH\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
(Cao et al., 2015)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD31(+), CD144(+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Function of EPC therapy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
EPCs can improve the function of RV\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Loisel et al., 2019)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD31(+), CD14(+), CD34(+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Function of EPC therapy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
EPCs show a no discernable therapeutic benefic\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Ormiston, Deng, Stewart, \& Courtman, 2010)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD31(+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Lung tissue\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Correlation between EPC and PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
number of EPCs is significantly reduced in PAH patients\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Duong et al., 2011)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
VEGFR-2(+), Tie2(+), CD14(+), CD31(+), CD34(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Bone marrow\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Function of EPC therapy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Both COX1-PGIS-EPCs and EPCs can alleviate PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Zhou et al., 2013)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
AC133(+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Correlation between EPC and PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
number of EPCs is significantly reduced in PAH patients\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(Junhui et al., 2008)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
CD34(+), CD133(+), VEGFR-2(+)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Correlation between EPC and lung disease\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Progenitor cell types are present in the neointima of occluded
vessels\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
(Yao et al., 2009)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CD34(+), CD144(+), CD31(+), VEGFR-2(+), eNOS (+)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Peripheral blood\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Function of EPC therapy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Inhibition of ROCK reduced EPCs senescence and alleviate PAH\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
(B. Liu et al., 2016)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

VEGFR-2, Vascular Endothelial Growth Factor Receptor-2, also known as
KDR (Kinase Insert Domain Receptor)/Flk-1(Fetal Liver Kinase 1); eNOS,
endothelial nitric oxide synthase; sca-1, Stem cells antigen-1; ZsGreen,
Zoanthus sp. green fluorescent protein; vWF, von Willebrand factor; NOX,
NADPH oxidase; ROCK, Rho-kinase;

\textbf{Table 2 Summary of recent literature regarding MSC therapy in
PAH}\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Cell} \textbf{source}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Application form}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Route}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Dosage}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Modeling}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Start time and end time}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Outcome}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Reference}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Mice UC\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Cell suspension\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IV\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5x10\textsuperscript{5} Cells in 50 \selectlanguage{greek}µ\selectlanguage{english}L PBS\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4 weeks hypoxia and 2 weeks hypoxia/SU5416\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treat at week 6, sacrifice at week 8\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treatment improves hemodynamic variables and histopathological
alterations of PAH models\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(Alencar et al., 2018)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Rat BM\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Cell suspension\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IV\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1\selectlanguage{ngerman}×10\textsuperscript{6} cells in 1 ml PBS\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3 weeks hypoxia /SU5416\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treat at week 1, Sacrifice at week 5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treatment improves hemodynamic variables and histopathological
alterations of PAH models\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(J. Huang et al., 2020)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Mice BM\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Exosome\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IV\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.1\selectlanguage{greek}µ\selectlanguage{english}g or 10\selectlanguage{greek}µ\selectlanguage{english}g Exo in PBS once a day\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3 weeks hypoxia\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treat at day 4, Sacrifice After week 4 hypoxia\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treatment improves hemodynamic variables and histopathological
alterations of PAH models\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(Lee et al., 2012)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Rat BM\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Microvesicle / Cell suspension\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IV\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MSCs once a day MSC-MVs once two days\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
One injection of MCT(50 mg/kg) for 3 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treat at week 4, Sacrifice at week 6.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treatment improves hemodynamic variables and histopathological
alterations of PAH models\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(J. Y. Chen et al., 2014)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Rat AD\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Cell suspension\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IV\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10\textsuperscript{5} cells in 50 \selectlanguage{greek}µ\selectlanguage{english}l saline\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
One injection of MCT (60 mg/kg) for 2 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treat at week 2, Sacrifice at week 4\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treatment improves hemodynamic variables and histopathological
alterations of PAH models\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(de Mendon\selectlanguage{ngerman}ça et al., 2017)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Rat BM\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Cell suspension\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IV\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3 \selectlanguage{ngerman}× 10\textsuperscript{6} cells in PBS\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
One injection of MCT (50 mg/kg) for 3 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treat at week 4, Sacrifice at week 6\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treatment improves hemodynamic variables and histopathological
alterations of PAH models .\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(Cheng et al., 2017)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Rat BM\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Cell suspension\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IT\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3 \selectlanguage{ngerman}× 10\textsuperscript{6} cells in PBS\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
One injection of MCT (60mg/kg) for 2 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treat at week 3, Sacrifice at week 7\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treatment improves hemodynamic variables and histopathological
alterations of PAH models\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(Baber et al., 2007)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Rat BM\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Cell suspension\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IV\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1 \selectlanguage{ngerman}× 10\textsuperscript{5} cells in 0.1 mL LR\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hyperoxia for 15 days\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treat at day 5, Sacrifice at day 15\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Treatment improves hemodynamic variables and histopathological
alterations of PAH models\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(Suzuki et al., 2020)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

UC, umbilical cord; BM, bone marrow; AD, adipose derived; IV,
intravenous; IT, intratracheal; MSC, mesenchymal stem cell; MV,
microvesicle; PBS, phosphate buffer saline; MCT, monocrotaline; EV,
extracellular vesicle; LR, lactated Ringer's solution

\textbf{Table 3.} Summary of recent stem cell therapy clinical trials\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{NCT} \textbf{number}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Participants number}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{phase}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{intervention}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Cell type}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Study target}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Status}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NCT00641836\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
98\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Not Applicable\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Transplantation\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
EPC\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
The ideal quantity, duration and potential toxicity of therapy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
completed\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NCT03001414\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
45\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2 and 3\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Transfection and transplantation\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
EPC\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
establish the efficacy and safety of repeated monthly dosage\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Recruiting\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NCT00491309\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
45\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Not Applicable\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Evaluation\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
EPC\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Evaluate the effectivity and safety of low-dose training program\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Recruiting\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NCT00551408\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Not Applicable\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Evaluation\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
EPC\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Establish the correlation between PAH and EPC\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Completed\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NCT04055415\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
60\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1 and 2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Transplantation\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MSC\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
establish the efficacy and safety of stem cell therapy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Recruiting\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NCT04432545\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
unknown\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Not Applicable\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Transplantation\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MSC\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
establish the efficacy and safety of stem cell therapy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Available\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-1/figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-2/figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-3/figure-3}

\end{center}
\end{figure}

\textbf{Hosted file}

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\textbf{Hosted file}

\verb`table2.doc`  available at \url{https://authorea.com/users/737918/articles/712545-stem-cell-therapy-in-pulmonary-arterial-hypertension-current-practice-and-future-opportunities}

\textbf{Hosted file}

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\selectlanguage{english}
\FloatBarrier
\end{document}

