Therapeutic applications differentiation of stem cells into vascular endothelial cells
Therapeutic applications differentiation of stem cells into vascular endothelial cells
Zohreh Farrar,1Niloofar Dehghan,2Tuba Zendeboudi,3Fatemeh Mohajer,4Fatemeh Madadi,5Neda Baghban,6,*
1. The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran 2. Student Research and Technology Committee, Bushehr University of Medical Sciences, Bushehr, Iran 3. The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran 4. The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran 5. The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran 6. The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
Introduction: Vascular endothelial cells derived from stem cells have substantial potential for the development of novel vascular therapeutics and cell-based therapies for the repair of ischemic damage. For instance, atherosclerosis is a slowly progressing and multifactorial disease, in which endothelial dysfunction and damage play an initial role. Following endothelial death, the neighboring mature endothelial cells actively proliferate and migrate to heal the wound. Therefore, with the rapid development of stem cell research, it is expected that stem/progenitor cells may serve as a new source for vascular repair. Therefore, this study aims to review the in vitro and in vivo differentiation of stem cells into endothelial cells for therapeutic applications.
Methods: This study is a review article with the use of a systematic search in valid databases such as ScienceDirect, EBSCO, ProQuest, and PubMed which were done in 2012-2022.
Results: It is demonstrated that vascular endothelial growth factor-A (VEGF-A) plays important role in cell differentiation and proliferation since it is an endothelial cell-specific mitogen produced by various cell types such as mesenchymal stem cells (MSCs), Totipotent embryonic stem (ES) cells, and adipose stromal cells. VEGF-A, the most important member of the VEGF family, mediates angiogenesis and cell differentiation.
While there is no conclusive marker for endothelial progenitor cells (EPCs), it is currently believed that the cells could be EPCs if they are double positive for markers including CD34, CD133, or VEGFR2 and murine EPCs as CD34, c-Kit, Sca-1 or Flk-1. Especially that temporal and spatial expressions of both Flk-1 and VEGF correlates with vasculogenesis in the embryo. In the cell culture system, embryonic stem (ES) cells can also undergo hematopoietic differentiation in a similar way to that found in the yolk sac and early fetal liver. Endogenous EPCs have multiple origins including bone marrow, spleen, intestine, liver, adipose tissue, and adventitia. But bone marrow is the most defined source of circulating EPCs. CD133+ Hematopoietic stem cells (HSCs) and CD34+ HSCs isolated from peripheral blood can differentiate into endothelial cells in vitro and contribute to vascularization in animal models. After release from bone marrows, EPCs are mobilized to their destination via cytokines such as stromal cell-derived factor (SDF)-1, nitric oxide, and VEGF, then they are retained on the vascular surface by binding to adhesion molecules. Once attached to the surface of the injured endothelium/vessel, EPCs undergo differentiation into ECs, in which the local micro-environment affects this process. Furthermore, mature ECs co-culture can also direct peripheral blood EPC differentiation toward endothelial phenotype.
Besides MSCs, human adipose stromal cells are multipotent cells with pericytic properties that can stabilize vascular assembly in vitro. This reciprocal production resulted in angiogenesis and adipose stromal cell-mediated reduction of EPC apoptosis. additionally, PDGF-BB secretion by ECs and VEGF production by adipose stromal cells play a role in the process.
Moreover, miRNAs are known to play important roles in maintaining stem cell pluripotency and regulating endothelial cell function and may play a role in angiogenesis.
The last factor is hypoxia which upregulates several genes involved in angiogenesis like basic fibroblast growth factor, VEGF, the VEGF receptors KDR and FLT-1, and components of the plasminogen system.
Conclusion: The isolation of MSCs makes them ideal tools for autologous or allogeneic cell therapy. The use of autologous vascular endothelial progenitor cells seems attractive for the development of engineered vessels as well as for the vascularization of engineered tissues and may also be useful to augment vessel growth in ischemic tissue. The mentioned factors in the study can potentially provide therapeutic benefits in pathological conditions that involve endothelial cells, such as wound repair, angiogenesis in ischemic tissues, microvascular permeability, vascular protection, and hemostasis and these findings may promote the understanding of tissue repair mechanisms and may lead to the development of novel strategies for therapeutic interventions aimed at ischemic diseases.