Human umbilical cord mesenchymal stem cells alleviate interstitial fibrosis and cardiac dysfunction in a dilated cardiomyopathy rat model by inhibiting TNF‑α and TGF‑β1/ERK1/2 signaling pathways

Abstract

Dilated cardiomyopathy (DCM) is a disease of the heart characterized by pathological remodeling, including patchy interstitial fibrosis and degeneration of cardiomyocytes. In the present study, the beneficial role of human umbilical cord-derived mesenchymal stem cells (HuMSCs) derived from Wharton's jelly was evaluated in the myosin-induced rat model of DCM. Male Lewis rats (aged 8-weeks) were injected with porcine myosin to induce DCM. Cultured HuMSCs (1×106 cells/rat) were intravenously injected 28 days after myosin injection and the effects on myocardial fibrosis and the underlying signaling pathways were investigated and compared with vehicle-injected and negative control rats. Myosin injections in rats (vehicle group and experimental group) for 28 days led to severe fibrosis and significant deterioration of cardiac function indicative of DCM. HuMSC treatment reduced fibrosis as determined by Masson's staining of collagen deposits, as well as quantification of molecular markers of myocardial fibrosis such as collagen I/III, profibrotic factors transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), and connective tissue growth factor (CTGF). HuMSC treatment restored cardiac function as observed using echocardiography. In addition, western blot analysis indicated that HuMSC injections in DCM rats inhibited the expression of TNF-α, extracellular-signal regulated kinase 1/2 (ERK1/2) and TGF-β1, which is a master switch for inducing myocardial fibrosis. These findings suggested that HuMSC injections attenuated myocardial fibrosis and dysfunction in a rat model of DCM, likely by inhibiting TNF-α and the TGF-β1/ERK1/2 fibrosis pathways. Therefore, HuMSC treatment may represent a potential therapeutic method for treatment of DCM.

Mesenchymal Stem/Stromal Cell-Based Therapy for Heart Failure ― What Is the Best Source? ―

“…89 Having said this, the major mechanism for UC-MSC-derived myocardial recovery in vivo is again believed to be the paracrine effect. 86 Paracrine effects of UC-MSC include increased angiogenesis, 84-86 decreased apoptosis, 84,86 reduction in fibrosis, 83,86 immunosuppression, 85 and recruitment and differentiation of endogenous cardiac stem cells. 84 These are likely to collectively result in increased global cardiac function 83,85,86 and prevention of ventricular dilatation.…”

“…86 Paracrine effects of UC-MSC include increased angiogenesis, 84-86 decreased apoptosis, 84,86 reduction in fibrosis, 83,86 immunosuppression, 85 and recruitment and differentiation of endogenous cardiac stem cells. 84 These are likely to collectively result in increased global cardiac function 83,85,86 and prevention of ventricular dilatation. 83,84 Of note, 1 study has demonstrated that UC-MSCs have a putative higher tissue-repair paracrine potential compared with adult tissuederived MSCs.…”

“…84 These are likely to collectively result in increased global cardiac function 83,85,86 and prevention of ventricular dilatation. 83,84 Of note, 1 study has demonstrated that UC-MSCs have a putative higher tissue-repair paracrine potential compared with adult tissuederived MSCs. 81 UC-MSC-mediated myocardial repair has been observed not only in ischemic heart disease models such as AMI and ICM, but also in nonischemic DCM models.…”

“…81 UC-MSC-mediated myocardial repair has been observed not only in ischemic heart disease models such as AMI and ICM, but also in nonischemic DCM models. 83 Based on these promising results from preclinical studies, clinical trials have been conducted since the early 2010 s. To date, 7 clinical trials have tested human UC-MSCs for the treatment of AMI and chronic HF, including both ICM and nonischemic cardiomyopathy ( Table 3). 81,90-95 A full range of IC, IM and IV injections were used as the celldelivery route.…”

Evaluation of platelet lysate as a substitute for FBS in explant and enzymatic isolation methods of human umbilical cord MSCs

“…Mesenchymal stem cells (MSCs) have acquired a prominent role in cell therapy strategies as they encompass pro-angiogenic 1 , anti-apoptotic 2 , anti-fibrotic 3 , anti-inflammatory 4 and tissue regenerative properties 5 . Furthermore, MSCs are unhindered by concerns of graft versus host disease (GVHD), formation of teratomas 6 , and ethical concerns 7 .…”