Abstract
Pulmonary arterial hypertension (PAH) is a chronic disease that is
characterized as mean pulmonary artery hypertension (mPAP)
> 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.
Key words: stem cell, pulmonary arterial hypertension,
mesenchymal stem cell, endothelial progenitor cell, therapy
Introduction
Pulmonary arterial hypertension (PAH) is a chronic disease that is
characterized as mean pulmonary artery hypertension (mPAP)>
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).