Mesenchymal stem cells to treat diabetic neuropathy: a long and strenuous way from bench to the clinic

Cell Death Discovery



Cell Death Discovery (2016) 2, e16055; doi:10.1038/cddiscovery.2016.55; published online 11 July 2016

JY Zhou1, Z Zhang1 and GS Qian2



As one of the most common complications of diabetes, diabetic neuropathy often causes foot ulcers and even limb amputations. Inspite of continuous development in antidiabetic drugs, there is still no efficient therapy to cure diabetic neuropathy. Diabetic neuropathy shows declined vascularity in peripheral nerves and lack of angiogenic and neurotrophic factors. Mesenchymal stem cells (MSCs) have been indicated as a novel emerging regenerative therapy for diabetic neuropathy because of their multipotency. We will briefly review the pathogenesis of diabetic neuropathy, characteristic of MSCs, effects of MSC therapies for diabetic neuropathy and its related mechanisms. In order to treat diabetic neuropathy, neurotrophic or angiogenic factors in the form of protein or gene therapy are delivered to diabetic neuropathy, but therapeutic efficiencies are very modest if not ineffective. MSC treatment reverses manifestations of diabetic neuropathy. MSCs have an important role to repair tissue and to lower blood glucose level. MSCs even paracrinely secrete neurotrophic factors, angiogenic factors, cytokines, and immunomodulatory substances to ameliorate diabetic neuropathy. There are still several challenges in the clinical translation of MSC therapy, such as safety, optimal dose of administration, optimal mode of cell delivery, issues of MSC heterogeneity, clinically meaningful engraftment, autologous or allogeneic approach, challenges with cell manufacture, and further mechanisms.



DN frequently leads to foot ulcers and ultimately limb amputations without effective clinical therapy. DN is characterized by reduced vascularity in the peripheral nerves and deficiency in angiogenic and neurotrophic factors. Only delivering neurotrophic or angiogenic factors for treatment in the form of protein or gene therapy is very modest if not ineffective. MSCs have been highlighted as a new emerging regenerative therapy owing to their multipotency for DN. MSCs reverse manifestations of DN, repair tissue, and antihyperglycemia. MSCs also paracrinely secrete neurotrophic factors, angiogenic factors, cytokines, and immunomodulatory substances to ameliorate DN. Challenges in the clinical translation of MSC therapy include safety, optimal dose of administration, optimal mode of cell delivery, issues of MSC heterogeneity, clinically meaningful engraftment, autologous or allogeneic approach, challenges with cell manufacture, and further mechanisms. therapy to DN in animal models,4 but gene therapy shows weak result or is ineffective. MSCs have been believed as a promising regenerative therapy for DN because of their multipotency and their paracrine secretion of angiogenic factors and neurotrophic factors. Umbilical cord blood ex vivo expanded CD34 and umbilical cord matrix MSCs were well tolerated without adverse effects in a 29-year-old male.5 MSC therapies offer more benefits than other cell-based therapies. Practically, as the safety of autologous bone marrow-derived MSCs (BMSCs) have been documented by variety of clinical trials,6 it is highly recommended to use this strategy in a pilot clinical trial for those who are severely affected by DN. In this review, we will briefly summarize the pathogenetic mechanisms, effects of MSC treatment, and challenges from bench to bedside studies of MSCs on DN.


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