Metformin impairs homing ability and efficacy of mesenchymal stem cells for cardiac repair in streptozotocin-induced diabetic cardiomyopathy in rats

Abstract

Bone marrow derived mesenchymal stem cells (BM-MSCs) have demonstrated potential in treating diabetic cardiomyopathy. However, diabetic patients are on multiple drugs and there is lack of understanding on how transplanted stem cells would respond in presence of such drugs. Metformin is an AMP Kinase (AMPK) activator, the widest used anti-diabetic drug. In this study, we investigated the effect of metformin on the efficacy of stem cell therapy in a diabetic cardiomyopathy animal model using streptozotocin (STZ) in male Wistar rats. To comprehend the effect of metformin on the efficacy of BM-MSCs, we transplanted BM-MSCs (1 million cells/rat) with or without metformin. Our data demonstrate that transplantation of BM-MSCs prevented cardiac fibrosis and promoted angiogenesis in diabetic hearts. However, metformin supplementation downregulated BM-MSCs mediated cardioprotection. Interestingly, both BM-MSCs and metformin treatment individually, improved cardiac function with no synergistic effect of metformin supplementation along with BM-MSCs. Investigating the mechanisms of loss of efficacy of BM-MSCs in the presence of metformin, we found that metformin treatment impairs homing of implanted BM-MSCs in the heart and leads to poor survival of transplanted cells. Furthermore, our data demonstrate that metformin mediated activation of AMPK is responsible for poor homing and survival of BM-MSCs in the diabetic heart. Hence, current study confirms that a conflict arises between metformin and BM-MSCs for treating diabetic cardiomyopathy. Approximately 10% of the world population is diabetic to which metformin is prescribed very commonly. Hence, future cell replacement therapies in combination with AMPK inhibitors may be more effective for diabetic patients.

Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications

“…SCs-based therapies are widely used in the treatment of various diseases[ 14 - 18 ]. Limbal stem cell therapy is used for treating burn-related corneal destruction[ 19 ], NSCs in gastrointestinal tract disorders[ 20 ], bone marrow-derived mesenchymal SCs (BM-MSCs) in diabetic cardiomyopathy[ 21 ], and MSCs in multiple sclerosis[ 22 ] and several clinical conditions. However, SC-based therapies also have limitations.…”

“…Exploring cell death mechanisms in SCs and targeting these potential therapeutic molecules are vital to successful SC-based therapies (shown in Table 1 [ 19 - 21 , 46 - 92 ]). In this review, we highlight the conditions or reasons leading to cell death in SC-based therapeutic approaches.…”

Mesenchymal Stem Cell Therapy in Diabetic Cardiomyopathy

“…When considering a possible translation to clinical practice, it is important to evaluate the interactions between MSCs transplantation and the standard diabetes therapeutic strategies. In a recent work, Ammar and colleagues investigated the effects of BM-MSCs therapy in STZ rats that were also treated with metformin [ 110 ], currently the most used antidiabetic drug. Metformin reduced the cardioprotective effects and glucose control induced by intravenous BM-MSCs therapy.…”

Mesenchymal Stem Cells Therapies on Fibrotic Heart Diseases

“…Attenuation of the pro-fibrotic FRP/Wnt/β-catenin pathway was induced by BM-MSCs preconditioned with resveratrol (RSV) resulting in enhanced cardioprotective and antifibrotic effects in diabetic cardiomyopathy [ 103 ]. Surprisingly, the most frequently prescribed antidiabetic drug, Metformin, impaired BM-MSC-mediated cardioprotection in diabetic cardiomyopathy by decreasing homing and survival of injected cells in the myocardium [ 104 ]. The efficacy of cell therapy with AT-MSCs in ameliorating myocardial inflammation and fibrosis in diabetic cardiomyopathy was explained by the macrophage polarization to the M2 phenotype in heart tissue and inhibition of the increase of IL-6 and TNF-α level, simultaneously increasing IL-10.…”