Hypoxic Preconditioning Improves the Therapeutic Potential of Aging Bone Marrow Mesenchymal Stem Cells in Streptozotocin-Induced Type-1 Diabetic Mice

Abstract

Insulin replacement is the current therapeutic option for type-1 diabetes. However, exogenous insulin cannot precisely represent the normal pattern of insulin secretion. Another therapeutic strategy is transplantation of pancreatic islets, but this is limited by immune rejection, intrinsic complications, and lack of donor availability. Stem cell therapy that results in the regeneration of insulin-producing cells represents an attractive choice. However, with advancing age, stem cells also undergo senescence, which leads to changes in the function of various cellular processes that result in a decrease in the regeneration potential of these aging stem cells. In this study, the effect of young and aging mesenchymal stem cells (MSCs) on the regeneration of pancreatic beta cells in streptozotocin (STZ)-induced type-1 diabetic mice was observed after hypoxic preconditioning. Hypoxia was chemically induced by 2, 4-dinitrophenol (DNP). Plasma insulin and glucose levels were measured at various time intervals, and pancreatic sections were analyzed histochemically. The effect of DNP was also analyzed on apoptosis of MSCs by flow cytometry and on gene expression of certain growth factors by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). We observed that hypoxic preconditioning caused changes in the gene expression levels of growth factors in both young and aging MSCs. Young MSCs showed significant regeneration potential compared with the aging cells in vivo. However, hypoxic preconditioning was able to improve the regeneration potential of aging MSCs. It is concluded from the present study that the regeneration potential of aging MSCs into pancreatic β-cells can be enhanced by hypoxic preconditioning, which causes changes in the gene expression of certain growth factors.

Role of Hyperglycemia in the Senescence of Mesenchymal Stem Cells

“…For example, the histone acetylase activator pentadecylidenemalonate 1b (SPV106) has been shown to alleviate cellular senescence and recover the regenerative and multi-differentiation potential of cardiac MSCs by restoring normal amounts of H3K9Ac and H3K14Ac and reducing DNA CpG hypermethylation (Vecellio et al, 2014). In addition, hypoxic preconditioning was able to enhance the regeneration potential of aging bone marrow MSCs into pancreaticβ-cells in streptozotocin-induced type-1 diabetic mice by altering gene expression levels of certain growth factors (Waseem et al, 2016). The underlying molecular mechanism might be related to hypoxia, which induces different regulation patterns in many cell cycle checkpoint genes such as HIF-1a, ataxia telangiectasia mutated, and ataxia telangiectasia and Rad3 related p53, p21, p27, and p21 (Sharma and Bhonde, 2015).…”

Hypoxic Preconditioning Eliminates Differences in the Innate Resistance of Rats to Severe Hypoxia

“…Thus, for the hypoxic preconditioning efficiency predicting and study of innate adaptive mechanisms, it is necessary to look for other, non-stressor methods for the separation of animals in their sensitivity to adaptive hypoxia. This will help to better understand the mechanisms of hypoxic preconditioning and to identify additional novel therapeutic targets for diverse acute and, possibly, chronic pathologies [13] [39].…”

Advanced protein adsorption properties of a novel silicate-based bioceramic: A proteomic analysis

“…The absence of IGF1 of mice has shown a significant decrease of bone formation and mineralization [ 42 ]. The in vivo study has found that the total amount and local expression level of IGF1 in bone tissue obviously reduced with the increase of age [ 43 , 44 ]. In another work, the overexpression of IGF1 in aging bmMSCs has accelerated the appearance of cell clusters at the area of bone defect, and thus promoted the expression of osteogenic related genes and enhanced mineralization process [ 45 ].…”