Sávio-Silva Christian, Beyerstedt Stephany, Soinski-Sousa Poliana E, Casaro Expedito B, Balby-Rocha Maria Theresa A, Simplício-Filho Antônio, Alves-Silva Jamille, Rangel Érika B
Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
Nephrology Division, Federal University of São Paulo, São Paulo, SP, Brazil.
Stem Cells Int. 2020 Nov 20;2020:8833725. doi: 10.1155/2020/8833725. eCollection 2020.
Diabetic kidney disease (DKD) is a microvascular complication of diabetes mellitus (DM) and comprises multifactorial pathophysiologic mechanisms. Despite current treatment, around 30-40% of individuals with type 1 and type 2 DM (DM1 and DM2) have progressive DKD, which is the most common cause of end-stage chronic kidney disease worldwide. Mesenchymal stem cell- (MSC-) based therapy has important biological and therapeutic implications for curtailing DKD progression. As a chronic disease, DM may impair MSC microenvironment, but there is compelling evidence that MSC derived from DM1 individuals maintain their cardinal properties, such as potency, secretion of trophic factors, and modulation of immune cells, so that both autologous and allogeneic MSCs are safe and effective. Conversely, MSCs derived from DM2 individuals are usually dysfunctional, exhibiting higher rates of senescence and apoptosis and a decrease in clonogenicity, proliferation, and angiogenesis potential. Therefore, more studies in humans are needed to reach a conclusion if autologous MSCs from DM2 individuals are effective for treatment of DM-related complications. Importantly, the bench to bedside pathway has been constructed in the last decade for assessing the therapeutic potential of MSCs in the DM setting. Laboratory research set the basis for establishing further translation research including preclinical development and proof of concept in model systems. Phase I clinical trials have evaluated the safety profile of MSC-based therapy in humans, and phase II clinical trials (proof of concept in trial participants) still need to answer important questions for treating DKD, yet metabolic control has already been documented. Therefore, randomized and controlled trials considering the source, optimal cell number, and route of delivery in DM patients are further required to advance MSC-based therapy. Future directions include strategies to reduce MSC heterogeneity, standardized protocols for isolation and expansion of those cells, and the development of well-designed large-scale trials to show significant efficacy during a long follow-up, mainly in individuals with DKD.
糖尿病肾病（DKD）是糖尿病（DM）的一种微血管并发症，其病理生理机制涉及多个因素。尽管有目前的治疗方法，但1型和2型糖尿病（DM1和DM2）患者中仍有30%-40%会发生进行性DKD，这是全球终末期慢性肾病最常见的病因。基于间充质干细胞（MSC）的治疗对于遏制DKD进展具有重要的生物学和治疗意义。作为一种慢性疾病，DM可能会损害MSC微环境，但有确凿证据表明，来自DM1个体的MSC仍保持其基本特性，如分化潜能、营养因子分泌以及免疫细胞调节能力，因此自体和异体MSC都是安全有效的。相反，来自DM2个体的MSC通常功能失调，表现出更高的衰老和凋亡率，克隆形成能力、增殖能力和血管生成潜能下降。因此，若要得出DM2个体的自体MSC对治疗DM相关并发症是否有效的结论，还需要更多人体研究。重要的是，在过去十年中已经构建了从实验室到临床的路径，以评估MSC在糖尿病环境中的治疗潜力。实验室研究为进一步开展转化研究奠定了基础，包括临床前开发和模型系统中的概念验证。I期临床试验评估了基于MSC治疗在人体中的安全性，II期临床试验（试验参与者的概念验证）仍需回答治疗DKD的重要问题，不过代谢控制已有记录。因此，还需要针对糖尿病患者开展考虑细胞来源、最佳细胞数量和给药途径的随机对照试验，以推进基于MSC的治疗。未来的方向包括减少MSC异质性的策略、这些细胞分离和扩增的标准化方案，以及开展精心设计的大规模试验，以在长期随访中显示出显著疗效，主要针对DKD患者。
