Abstract
BackgroundAngiogenesis is the main therapeutic mechanism of cell therapy for cardiovascular diseases, but diabetes is reported to reduce the function and number of progenitor cells. Therefore, we studied the effect of streptozotocin-induced diabetes on the bone marrow-mesenchymal stem cell (MSC) function, and examined whether diabetes-impaired MSC could be rescued by pretreatment with oxytocin.ResultsMSCs were isolated and cultured from diabetic (DM) or non-diabetic (non-DM) rat, and proliferation rate was compared. DM-MSC was pretreated with oxytocin and compared with non-DM-MSC. Angiogenic capacity was estimated by tube formation and Matrigel plug assay, and therapeutic efficacy was studied in rat myocardial infarction (MI) model.The proliferation and angiogenic activity of DM-MSC were severely impaired but significantly improved by pretreatment with oxytocin. Krüppel-like factor 2 (KLF2), a critical angiogenic factor, was dramatically reduced in DM-MSC and significantly restored by oxytocin. In the Matrigel plug assay, vessel formation of DM-BMSCs was attenuated but was recovered by oxytocin. In rat MI model, DM-MSC injection did not ameliorate cardiac injury, whereas oxytocin-pretreated DM-MSC improved cardiac function and reduced fibrosis.ConclusionsOur results show that diabetes influenced MSC by reducing angiogenic capacity and therapeutic potential. We demonstrate the striking effect of oxytocin on stem cell dysfunction and suggest the use of oxytocin as a priming reagent in autologous stem cell therapy.
Highlights
Angiogenesis is the main therapeutic mechanism of cell therapy for cardiovascular diseases, but diabetes is reported to reduce the function and number of progenitor cells
Proliferation is reduced in Diabetes mellitus (DM)-mesenchymal stem cell (MSC) and recovered by oxytocin Hyperglycemia was induced 4 weeks after streptozotocin injection (Table 1), and the mortality was 29.17% in the diabetic group
Bone marrowMSCs were isolated from non-DM rats
Summary
Angiogenesis is the main therapeutic mechanism of cell therapy for cardiovascular diseases, but diabetes is reported to reduce the function and number of progenitor cells. Cell therapy with autologous bone marrow-mesenchymal stem cells (MSC) is a promising and safe modality with the potential for vascular regeneration in the treatment of ischemic diseases. Obesity, or aging influence stem cell numbers and activities [6,7,8,9,10,11], the animal studies could not predict the outcomes of autologous stem cell therapy for a patient with diabetes or other risk factors [12,13]. There is no doubt that diabetes is not the only factor associated with dysfunction of progenitor cells, but diabetes leads to significant cellular dysfunction such as poor migration, reduced proliferation, and poor vascular network formation [7]. Diabetes-related changes in stem cells or progenitor cells may account for the reduced proliferation rate of these cells and for their limited angiogenic potential [18]
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