Effects of reprogrammed and engineered MSCs on diabetic complications

 糖尿病是一个迅速增长的全球性健康问题。虽然糖尿病神经病变（DN）和外周动脉疾病（PAD）是最常见的并发症，但没有有效的治疗方法。糖尿病神经病变（DN）影响60%的糖尿病患者，并且其特征在于对神经血管以及神经元细胞的损害。糖尿病中的晚期PAD经常影响小血管，使得传统的介入和手术治疗无效，并且经常导致肢体丧失。研究表明，骨髓间充质干细胞（MSCs）可有效治疗心血管疾病和糖尿病肾病。然而，据报道，来自糖尿病受试者的MSC功能较弱，并且表观遗传染色质变化被认为是这种功能障碍的基础。新出现的证据表明，小分子表观遗传修饰剂可以改变关键的染色质重塑酶和改变细胞功能。细胞治疗的另一个主要问题是体内细胞滞留率低，已经出现了一种生物工程方法来克服这一缺陷。因此，我们建议使用小分子表观遗传修饰剂恢复糖尿病间充质干细胞的功能，并将这些重编程的糖尿病间充质干细胞与生物材料结合用于治疗糖尿病神经和血管并发症。然后，我们将确定它们对糖尿病PAD和DN的良好动物模型的治疗效果。我们预计，这项研究将产生新的见解骨髓间充质干细胞在糖尿病中的染色质改变，并建议潜在的治疗效用的重编程骨髓间充质干细胞治疗各种糖尿病相关的神经和血管并发症，在自体的方式。鉴于MSC的安全性，一旦本研究确定了疗效，这种方法就可以很容易地转化为先导性临床试验。

 DESCRIPTION: Diabetes is a rapidly growing global health problem. While diabetic neuropathy (DN) and peripheral arterial disease (PAD) are among the most common complications, there are no effective therapies. Diabetic neuropathy (DN) affects 60% of diabetic patients, and is characterized by damage to the neural vasculature as well as to neuronal cells. Advanced PAD in diabetes frequently affects small vessels such that conventional interventional and surgical treatments are ineffective, and frequently leads to limb loss. Studies have shown that bone marrow-derived mesenchymal stem cells (MSCs) are effective in treating cardiovascular diseases and DN. However, MSCs derived from diabetic subjects were reported to be less functional, and epigenetic chromatin changes were suggested to underlie this dysfunction. Emerging evidence has shown that small molecular epigenetic modifiers can change key chromatin remodeling enzymes and alter cellular function. Another main problem for cell therapy is low cell retention in vivo and a bioengineering approach has emerged to overcome this pitfall. Accordingly, we propose to restore the function of diabetic MSCs using small molecular epigenetic modifiers and apply these reprogrammed diabetic MSCs in combination with biomaterials for the treatment of diabetic neural and vascular complications. We will then determine their therapeutic effects on well-established animal models of diabetic PAD and DN. We anticipate that this study will yield novel insight into the chromatin alterations of MSCs in diabetes and suggest the potential therapeutic utility of reprogrammed MSCs for treating various diabetes-related neural and vascular complications in an autologous manner. Given the safety of MSCs, this approach can be easily translated into a pilot clinical trial once the efficacy is established by this study.