Type 2 Diabetes Mellitus Duration and Obesity alter the Efficacy of Autologously Transplanted Bone Marrow-derived Mesenchymal Stem/Stromal Cells

Abstract

Human bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) represent promising stem cell therapy for the treatment of type 2 diabetes mellitus (T2DM), but the results of autologous BM-MSC administration in T2DM patients are contradictory. The purpose of this study was to test the hypothesis that autologous BM-MSC administration in T2DM patient is safe and that the efficacy of the treatment is dependant on the quality of the autologous BM-MSC population and administration routes. T2DM patients were enrolled, randomly assigned (1:1) by a computer-based system into the intravenous and dorsal pancreatic arterial groups. The safety was assessed in all the treated patients, and the efficacy was evaluated based on the absolute changes in the hemoglobin A1c, fasting blood glucose, and C-peptide levels throughout the 12-month follow-up. Our data indicated that autologous BM-MSC administration was well tolerated in 30 T2DM patients. Short-term therapeutic effects were observed in patients with T2DM duration of <10 years and a body mass index <23, which is in line with the phenotypic analysis of the autologous BM-MSC population. T2DM duration directly altered the proliferation rate of BM-MSCs, abrogated the glycolysis and mitochondria respiration of BM-MSCs, and induced the accumulation of mitochondria DNA mutation. Our data suggest that autologous administration of BM-MSCs in the treatment of T2DM should be performed in patients with T2DM duration <10 years and no obesity. Prior to further confirming the effects of T2DM on BM-MSC biology, future work with a larger cohort focusing on patients with different T2DM history is needed to understand the mechanism underlying our observation.

Type 2 Diabetes Mellitus Facilitates Shift of Adipose-Derived Stem Cells Ex Vivo Differentiation toward Osteogenesis among Patients with Obesity

“…Some data suggest the suppression of differentiation potential and the upregulation of apoptosis and inflammation in ADSCs from patients with T2DM [ 9 ]. ADSCs from obesogenic and diabetic conditions have demonstrated the abrogation of glycolysis, OXPHOS metabolism, and the accumulation of mutations in mitochondrial DNA [ 10 ]. Moreover, ADSCs from T2DM patients have been found to exhibit lower proliferative activity and altered secretory profiles manifested as decreased VEGF, decreased adiponectin, and increased leptin secretion [ 11 , 12 ].…”

Human Adipose-Derived Mesenchymal Stromal Cells Exhibit High HLA-DR Levels and Altered Cellular Characteristics under a Xeno-free and Serum-free Condition

“…To evaluate the karyotype of ADMSCs after prolonged culture in vitro, passage 3 and 7 cells were checked for karyotype as previously described [26]. When the cells reached 80% confluence, they were incubated in KaryoMAX® Col-cemid™ 10 µl/ ml (Gibco, USA), diluted to 1:1000, at 37 °C in a 5% CO2 incubator for 30 min.…”

“…MSCs obtained from aged donors were associated with lower growth kinetics, increased senescence, and altered differentiation potential [22][23][24]. Metabolic diseases such as type 2 diabetes may restrict MSC functions [25,26]. Therefore, the influence of culture conditions and donor characteristics on MSC characteristics should be addressed.…”

Clinical Study of Mesenchymal Stem/Stromal Cell Therapy for the Treatment of Frailty: A Proposed Experimental Design for Therapeutic and Mechanistic Investigation

“…In vivo evidence suggests that BM-MSCs can be affected by aging and are strongly associated with the mammalian life span and health conditions ( 12 , 13 ). Recently, our group reported the negative effects of type 2 diabetes mellitus duration on the quality and metabolic function of autologous BM-MSCs ( 14 ). Hence, the variation in efficacy observed in a recent study using BM-MSCs for the treatment of frailty could be due to (i) the heterogeneous sources of BM-MSCs, which were derived from a wide age range of BM-MSC donors, (ii) the in vitro culture of BM-MSCs in fetal bovine serum (unknown component, batch-to-batch variation, and animal-derived products), and (iii) the aging-related effects of BM-MSCs.…”