The Relative Contribution of Paracine Effect versus Direct Differentiation on Adipose-Derived Stem Cell Transplantation Mediated Cardiac Repair

Abstract

BackgroundRecent studies have demonstrated that transplantation of adipose-derived stem cell (ADSC) can improve cardiac function in animal models of myocardial infarction (MI). However, the mechanisms underlying the beneficial effect are not fully understood. In this study, we characterized the paracrine effect of transplanted ADSC and investigated its relative importance versus direct differentiation in ADSC transplantation mediated cardiac repair.Methodology/Principal FindingsMI was experimentally induced in mice by ligation of the left anterior descending coronary artery. Either human ADSC, conditioned medium (CM) collected from the same amount of ADSC or control medium was injected into the peri-infarct region immediately after MI. Compared with the control group, both ADSC and ADSC-CM significantly reduced myocardial infarct size and improved cardiac function. The therapeutic efficacy of ADSC was moderately superior to ADSC-CM. ADSC-CM significantly reduced cardiomyocyte apoptosis in the infarct border zone, to a similar degree with ADSC treatment. ADSC enhanced angiogenesis in the infarct border zone, but to a stronger degree than that seen in the ADSC-CM treatment. ADSC was able to differentiate to endothelial cell and smooth muscle cell in post-MI heart; these ADSC-derived vascular cells amount to about 9% of the enhanced angiogenesis. No cardiomyocyte differentiated from ADSC was found.ConclusionsADSC-CM is sufficient to improve cardiac function of infarcted hearts. The therapeutic function of ADSC transplantation is mainly induced by paracrine-mediated cardioprotection and angiogenesis, while ADSC differentiation contributes a minor benefit by being involved in angiogenesis. Highlights 1 ADSC-CM is sufficient to exert a therapeutic potential. 2. ADSC was able to differentiate to vascular cells but not cardiomyocyte. 3. ADSC derived vascular cells amount to about 9% of the enhanced angiogenesis. 4. Paracrine effect is the major mechanism of ADSC therapeutic function for MI.

Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

“…Furthermore, a hypothesis of the current research is that enhanced myocardial repair is contingent on communication between injected stem cells and the cells within the heart. [12][13][14] This communication could come from secretion of cardioprotective factors (paracrine signaling) or from direct contact between stem cells and cardiomyocytes. Paracrine signaling between the donated stem cell population and host myocardium is important to promote cell-based myocardial repair.…”

Fibrin-based 3D matrices induce angiogenic behavior of adipose-derived stem cells

“…However, the question of which mechanism is more critical for achieving therapeutic benefit remains unanswered. A recent report demonstrated that ASCs transplanted to the myocardium, post infarct, decreased infarct-associated cell death and stimulated reperfusion of damaged heart tissue [47]. These benefits were linked to angiogenic paracrine secretion of ASCs, rather than trans-differentiation into cardiomyocytes [47].…”

Prospect of Stem Cell Conditioned Medium in Regenerative Medicine

“…The use of CM for therapy is very appealing and may be booming in the near future, as studies on the use of CM for various diseases are accumulating [1, 3–33]. Conditioned medium contains various growth factors and tissue regenerative agents, which were secreted by the stem cells.…”