Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease: A Review of the Studies Using Syngeneic, Autologous, Allogeneic, and Xenogeneic Cells

Abstract

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.

Therapeutic Potential of Mesenchymal Stem Cells in a Pre-Clinical Model of Diabetic Kidney Disease and Obesity

“…Consequently, alternative glucose metabolic pathways, including polyol and hexosamine biosynthetic pathways, are activated and increase ROS production, thus completing the vicious circle of cellular oxidative stress. There is an increasing body of evidence showing the potential of MSCs as an effective anti-oxidative therapeutic tool against DKD progression [ 61 , 62 ]. However, our diabetic and obese mice exhibited severe hyperglycemia throughout the study, which could have abrogated MSC therapeutic potential in reducing oxidative stress.…”

“…However, our diabetic and obese mice exhibited severe hyperglycemia throughout the study, which could have abrogated MSC therapeutic potential in reducing oxidative stress. Importantly, MSC efficiency may be affected by other factors, such as the number of infusions, route of delivery, homing capacity, microenvironment, and the severity of the condition [ 62 ]. Therefore, MSCs systemically (intravenous) administrated have been clinically effective in reducing insulin intake of T2DM patients, with limited duration though [ 63 ], which could be explained by host factors, such as chronic hyperglycemia, sustained oxidative stress and inflammation, and by MSC properties, including being trapped in the lungs, lower levels of proliferation and migration, and higher rates of apoptosis and senescence in DM setting [ 62 ].…”

Allogeneic vs. autologous mesenchymal stem/stromal cells in their medication practice

“…Additionally, T1DM donor MSCs exhibited to be phenotypically and functionally similar to the health donor MSCs [ 81 ]. Furthermore, MSCs derived from T1DM patients can maintain their normal capability of secretion and immunomodulation and, however, MSCs from T2DM individuals may be usually dysfunctional such as the increased rates of senescence and apoptosis and the decreased proliferation and angiogenesis potential [ 82 ]. Therefore, while the current studies indicate that using autologous MSCs is likely to be suitable for T1DM therapy, the large scale trials still need to test autologous vs. allogeneic MSCs’ safety and efficacy in T1DM as well as T2DM.…”

Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease

“…Intra-arterial routes, including intra-aorta, intra-renal artery and intracarotid routes, are associated with a more robust repair of kidney injury. Although the intraparenchymal route, e.g., under the renal capsule, leads to kidney improvement, this route is less practical for clinical applications [256].…”

“…The evaluation of its therapeutic potential in the most appropriate pre-clinical model that mimics renal disease in humans is also of paramount importance for advancing our understanding of MSC-based therapy. Therefore, a large body of evidence has demonstrated the impact of this therapy in acute kidney injury, including IRI, kidney transplantation and drug-induced kidney injury [262], as well as chronic kidney disease, in particular DKD [256]. Whether the same kind of results is seen in humans with multiple comorbidities remains to be studied in detail.…”