Proangiogenic Features of Mesenchymal Stem Cells and Their Therapeutic Applications

Abstract

Mesenchymal stem cells (MSCs) have shown their therapeutic potency for treatment of cardiovascular diseases owing to their low immunogenicity, ease of isolation and expansion, and multipotency. As multipotent progenitors, MSCs have revealed their ability to differentiate into various cell types and could promote endogenous angiogenesis via microenvironmental modulation. Studies on cardiovascular diseases have demonstrated that transplanted MSCs could engraft at the injured sites and differentiate into cardiomyocytes and endothelial cells as well. Accordingly, several clinical trials using MSCs have been performed and revealed that MSCs may improve relevant clinical parameters in patients with vascular diseases. To fully comprehend the characteristics of MSCs, understanding their intrinsic property and associated modulations in tuning their behaviors as well as functions is indispensable for future clinical translation of MSC therapy. This review will focus on recent progresses on endothelial differentiation and potential clinical application of MSCs, with emphasis on therapeutic angiogenesis for treatment of cardiovascular diseases.

Figure 1

MSCs mediated therapy for myocardial infarction (MI). MSCs therapy could enhance heart function by (1) transdifferentiation into cardiomyocytes or endothelial cells (ECs) to replace the damage tissue and promote angiogenesis, respectively, (2) releasing soluble autocrine/paracrine factors, thereby activating endogenous adult cells involved in cells renewal/protection and neovascularization, and (3) stimulating endogenous resident cardiac stem cells (CSCs) proliferation and differentiation by paracrine soluble factors.

Figure 2

Intravital microscope analysis revealed that MSCs behaved like pericytes wrapping around the vessel in a tissue-engineered vascular model. With multiphoton laser scanning microscopy (MPLSM), images were taken at different time points. Lumen formation and blood flow in hMSCs (EGFP+) derived cells were not able to detect (a). On the contrary, implant HUVECs (DsRed+) and hMSCs (EGFP+) in mice, hMSCs (EGFP+) could be found elongate into thin slit structures and coalesced around the HUVEC-derived vessels (b)–(f). Over time, the number of interstitial hMSCs (EGFP+) was decreased, and most of them were associated with blood vessels by day 83 (g). Reprinted with permission from [60].

Figure 3

Angiogenic potency of MSCs. MSCs could promote angiogenesis either by paracrine effects or by transdifferentiation. The secretion of cytokines could enhance the proliferation and migration of endogenous endothelial cells. Moreover, MSCs may transdifferentiate into lineage with functional and phenotypic features of ECs and participate in angiogenesis directly.