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).