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.

中文翻译：

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二甲双胍损害间充质干细胞对链脲佐菌素诱导的糖尿病心肌病心脏修复的归巢能力和功效


骨髓间充质干细胞（BM-MSC）已被证明具有治疗糖尿病心肌病的潜力。然而，糖尿病患者正在服用多种药物，并且对于移植的干细胞在这些药物存在下如何反应缺乏了解。二甲双胍是一种 AMP 激酶 (AMPK) 激活剂，是使用最广泛的抗糖尿病药物。在这项研究中，我们在雄性 Wistar 大鼠中使用链脲佐菌素（STZ）研究了二甲双胍对糖尿病心肌病动物模型干细胞治疗效果的影响。为了了解二甲双胍对 BM-MSC 功效的影响，我们在有或没有二甲双胍的情况下移植了 BM-MSC（100 万个细胞/大鼠）。我们的数据表明，骨髓间充质干细胞移植可预防糖尿病心脏的心脏纤维化并促进血管生成。然而，补充二甲双胍下调了 BM-MSC 介导的心脏保护作用。有趣的是，BM-MSC 和二甲双胍单独治疗均可改善心脏功能，而补充二甲双胍与 BM-MSC 没有协同作用。研究二甲双胍存在下 BM-MSC 功效丧失的机制，我们发现二甲双胍治疗会损害植入的 BM-MSC 在心脏中的归巢，并导致移植细胞的存活率较差。此外，我们的数据表明，二甲双胍介导的 AMPK 激活是糖尿病心脏中 BM-MSC 归巢和存活不良的原因。因此，目前的研究证实二甲双胍和 BM-MSC 治疗糖尿病心肌病之间存在冲突。世界上大约 10% 的人口患有糖尿病，二甲双胍的处方非常普遍。因此，未来的细胞替代疗法与 AMPK 抑制剂相结合可能对糖尿病患者更有效。