Diabetes-induced glucolipotoxicity impairs wound healing ability of adipose-derived stem cells-through the miR-1248/CITED2/HIF-1α pathway

Abstract

Despite being an attractive cell type for mesenchymal stem cell (MSC) transplantation therapy for wound healing, human adipose-derived stem cells (hADSCs) from diabetes mellitus (DM) patients result in remarkable retention of stem cell activity due to diabetes-induced glucolipotoxicity. We explored the effect of diabetes and medium containing AGEs on the cell activity, phenotype, multipotency, angiogenic potential, and the therapeutic effect of hADSCs. Then, miRNA-1248 was selected by miRNA microarray analysis to further study the core molecular pathways that regulate the wound healing ability of hADSCs. hADSCs isolated from DM patients or cultured in medium containing AGEs in vitro exhibited decreased effectiveness in stem cell therapy. The expression of miRNA-1248 was decreased in the hADSCs of DM patients and hence failed to positively regulate stem cell activity, differentiation functions, and angiogenesis promotion effect. This concomitantly increased the expression of CITED2, an inhibitor of HIF-1α, thus influencing growth factors that promote angiogenesis, cellular proliferation, and wound healing. Overall, our data demonstrated that the glucolipotoxicity-impaired wound healing ability of hADSCs might occur through the miR-1248/CITED2/HIF-1α pathway. MiRNA-1248 may have potential to be used as a novel therapeutic target for wound healing in DM patients or restoring the wound healing ability of diabetic hADSCs.

Role of Hyperglycemia in the Senescence of Mesenchymal Stem Cells

“…Moreover, the expression of miRNA-1248 was reduced, paralleled by increased expression of CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), an inhibitor of HIF-1α, which influences growth factors that promote cellular proliferation, angiogenesis, and wound healing. Thus, the authors of the study concluded that glucolipotoxicity impaired the effectiveness of AMSCs through the miR-1248/CITED2/HIF-1α pathway (Xiao et al, 2020). As previously mentioned, several studies have shown that hyperglycemia reduces the osteogenic potential of MSCs.…”

“…In addition to the above features, MSCs in hyperglycemic conditions show decreased immunomodulatory properties (Montanucci et al, 2016), angiogenesis (Xiao et al, 2020), and migration (Liu Y. et al, 2020), but increased SASP and insulin resistance. SASP is mainly composed of various extracellular growth factors, cytokines/chemokines and receptor antagonists.…”

Promotion of Hair Growth by Conditioned Medium from Extracellular Matrix/Stromal Vascular Fraction Gel in C57BL/6 Mice

“…However, cells were almost excluded except for ADSCs after in vitro cell culture. In our previous studies, we found that the percentage of MSC-specific cell markers (CD90 + , CD73 + , or CD105 + ) in cultured SVF cells were more than 95%, while the percentage of hematopoietic-specific cell markers (CD34 -, CD11b -, CD19 -, or CD45 -) was negative [30][31][32]. In this study, CMs were collected from the medium of ECM/SVF and SVF after cultured for 48 h. Therefore, we consider that the biological efficacy of CMs mainly attributed to ADSCs.…”

Adipose Tissue-Derived Stem Cells Retain Their Adipocyte Differentiation Potential in Three-Dimensional Hydrogels and Bioreactors

“…Through the degradation of SP neurons, IPFP-ASCs could be used to manage pain and work in multiple ways to decrease inflammation. Previous literature suggests that obesity and type II diabetes mellitus alter ASC therapeutic properties; however, there are no studies as of yet that have investigated if these changes are found in IPFP-ASCs [ 49 , 50 ]. Therefore, IPFP-ASCs will be used to engineer adipose tissue for the knee-specific MPS.…”