Mesenchymal stem cells (MSCs) are self-renewing multipotent cells that have the capacity to secrete multiple biologic factors that can restore and repair injured tissues. Preclinical and clinical evidence have substantiated the therapeutic benefit of MSCs in various medical conditions. Currently, MSCs are the most commonly used cell-based therapy in clinical trials because of their regenerative effects, ease of isolation, and low immunogenicity. Experimental and clinical studies have provided promising results using MSCs to treat diabetes. This review will summarize the role of MSCs on tissue repair, provide emerging strategies to improve MSC function, and describe how these processes translate to clinical treatments for diabetes.
MESENCHYMAL STEM CELLS TO TREAT DIABETES
Safety Issue In 2015, investigators from Sweden reported the first study aimed to evaluate safety and efficacy of autologous MSC treatment in newly-diagnosed type 1 diabetics.They concluded that administration of MSCs did not result in adverse events in any of the 10 patients and provided promising C-peptide concentrations at the one-year follow-up.
Functional Differences Hu et al conducted a single-center double blind study examining the safety, feasibility, and preliminary outcomes of umbilical cord Wharton’s jelly-derived MSCs for new-onset type I diabetics. The MSC-treated group underwent two intravenous infusions. Postprandial glucose and HbA1c measurements were lower in the experimental cohort between 9 months to 24 months after MSC infusion. Also, insulin usage and fasting C-peptide were significantly improved in the MSC group. A pilot study in China involving placenta-derived MSCs to patients with long-standing diabetes mellitus type 2 revealed the transplantation was safe, easy, and potentially efficacious. This investigation included 10 patients with type 2 diabetes for a duration ≥3 years, insulin dependent (≥0.7 U/kg/day) for at least one year, and poorly controlled glucose. The subjects received on average 1.35 × 106/kg placental stem cells on three separate occasions with one-month intervals between intravenous infusions. Six months after treatment, the insulin dosage and HbA1c measurements for all the patients demonstrated a trend towards improvement. Moreover, C-peptide and insulin release were also higher after MSC treatment. In addition, this study included a group of individuals that translate closer to actual clinical scenarios, as they also had other co-morbidities, including heart disease, kidney disease, and vascular complications.
Therapeutic effects of mesenchymal stem cells
MSCs STIMULATE TISSUE REPAIR
It is well established that the beneficial outcomes of MSCs occur through a paracrine release of biologic factors, rather than engraftment of cells into the recipient tissue. For purposes of this review, studies examining the regenerative properties of MSCs will be generalized into the following major themes: vascular development, anti-inflammation, and anti-fibrosis .
Angiogenesis, the formation of new blood vessels, is a vital process in tissue wound healing that is a targeted by many pharmacologic agents to treat disorders such as myocardial ischemia, ischemic stroke, and diabetic retinopathy. Preclinical studies in cardiac and brain ischemia support the concept that MSCs improve structural and functional outcomes by repairing and stimulating the growth of blood vessels. The angiogenic properties of MSCs is mediated through the release of hypoxia inducible factor, vascular endothelial growth factor, angiopoietin, and erythropoietin. The ability to repair vascular injury after administration of MSCs has been supported in studies of diabetic peripheral vascular disease, cutaneous
wound repair, and bone necrosis .
Although inflammation is the body’s natural response to protect against harmful stimuli, excessive or prolonged inflammatory stress can be detrimental to cells and tissues. For instance, chronic inflammation has now emerged as an important contributor to the pathogenesis of metabolic syndrome. As such, investigators have begun exploring the interactions between inflammation and MSC therapy. In particular, MSCs modulate key inflammatory cell types, including T-cells, natural killer cells, B-cells, and dendritic cells . The MSC interaction with these innate and adaptive immune cells results in down regulation of inflammatory markers (interleukin-1β, tumor necrosis factor α, interleukin-6) as well as an increase in protective cytokines (interleukin-10, prostaglandin E2, indoleamine 2, 3-dioxygenase). Bone degenerative studies treated with MSCs also highlight their ability to decrease the secretion of macrophage inflammatory protein and monocyte chemoattractant protein. In rodent models of acute lung injury, Gupta et al demonstrated that MSCs increase expression of anti-inflammatory cytokine interleukin-10.
Multiple groups have documented the anti-fibrotic effects of MSCs. In a study of radiation-induced pulmonary fibrosis in Sprague Dawley rats, Dong et al showed a decrease in pro-fibrotic transforming growth factor-β and tumor necrosis factor-α after systemic MSC instillation. The authors speculate that MSCs also inhibit lung fibrosis through the secretion of hepatocyte growth factor and prostaglandin. Similarly, a review article of preclinical and clinical studies recapitulates the anti-fibrotic effects of MSCs in liver fibrosis.Taken together, the growing body of literature demonstrates the potential benefits MSCs may offer in endocrine disorders.