Mesenchymal Stem Cells Derived from Bone Marrow of Diabetic Patients Portrait Unique Markers Influenced by the Diabetic Microenvironment

Abstract

■ AbstractCellular microenvironment is known to play a critical role in the maintenance of human bone marrow-derived mesenchymal stem cells (BM-MSCs). It was uncertain whether BM-MSCs obtained from a 'diabetic milieu' (dBM-MSCs) offer the same regenerative potential as those obtained from healthy (non-diabetic) individuals (hBM-MSCs). To investigate the effect of diabetic microenvironment on human BMMSCs, we isolated and characterized these cells from diabetic patients (dBM-MSCs). We found that dBM-MSCs expressed mesenchymal markers such as vimentin, smooth muscle actin, nestin, fibronectin, CD29, CD44, CD73, CD90, and CD105. These cells also exhibited multilineage differentiation potential, as evident from the generation of adipocytes, osteocytes, and chondrocytes when exposed to lineage specific differentiation media. Although the cells were similar to hBM-MSCs, 6% (3/54) of dBM-MSCs expressed proinsulin/C-peptide. Emanating from the diabetic microenvironmental milieu, we analyzed whether in vitro reprogramming could afford the maturation of the islet-like clusters (ICAs) derived from dBM-MSCs. Upon mimicking the diabetic hyperglycemic niche and the supplementation of fetal pancreatic extract, to differentiate dBM-MSCs into pancreatic lineage in vitro, we observed rapid differentiation and maturation of dBM-MSCs into islet-like cell aggregates. Thus, our study demonstrated that diabetic hyperglycemic microenvironmental milieu plays a major role in inducing the differentiation of human BM-MSCs in vivo and in vitro.

Promise(s) of Mesenchymal Stem Cells as an In Vitro Model System to Depict Pre-Diabetic/Diabetic Milieu in WNIN/GR-Ob Mutant Rats

“…Interestingly, we have shown an increase in the number of ILCAs obtained from BM-MSCs derived from Mutants, suggestive of obese/obese-diabetic environment similar to the findings of Rosen et al, [39] and Sun et al, [54]. In support of these, we have also demonstrated a significantly upregulated expression of insulin (hyperinsulinemic) and a decreased PDX-1, (a transcription factor necessary for pancreatic development and β-cell maturation) and GLUT-2 (pancreatic glucose transporter) (Figure 4F) implicating for a hyperglycemic environment [18], [34], [55]. Such an ectopic expression of these genes in BM-MSCs possibly can be attributed to body’s adaptive mechanism in the management of hyperglycemia, since HI (increased insulin levels in circulation) precedes onset of IR and T2D [25], [27].…”

Mesenchymal stem cells improve survival in ischemic diabetic random skin flap via increased angiogenesis and VEGF expression

“…Cellular milieu plays an important function in the preservation of human BMMSCs. It has been confirmed that diabetic high glucose milieu plays a main role in encouraging human BMMSCs differentiation in vivo and in vitro . Notably, in DM, an ischemic flap prompts phenotypic alterations in BM‐derived endothelial progenitor cells that subsequently move via the blood vessel.…”

Clinical Islet Cell Transplantation – Recent Advances

“…bone marrow and adipose tissue, among other sources) and depending on cytokines and cell-cell interactions, can differentiate into various cell types that form bone, cartilage, adipose tissue, and hepatocytes. Phadnis et al 64 demonstrated that human bone marrow-derived mesenchymal stem cells can differentiate into endocrine pancreatic cells. In vivo, secretion of human C-peptide was present after transplantation of these cells into pancreatectomized and streptozotocin-induced diabetic mice; using transplantation of human bone marrow-derived mesenchymal stem cells, normoglycaemia could be maintained.…”