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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.

Keywords: autologous; autologous stem cell transplantation; bone marrow; diabetes.

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Conflict of interest statement

The authors indicated no potential conflicts of interest.

Figures

FIGURE 1

FIGURE 1

Treatment procedure for this trial.…

FIGURE 1

Treatment procedure for this trial. One hundred seven patients were screened to select…

FIGURE 1 Treatment procedure for this trial. One hundred seven patients were screened to select 30 patients who met all the inclusion criteria of the study. The patients were randomized into two groups divided based on the transplantation route: one group received stem cells via intravenous infusion, and the other group received stem cells through the dorsal pancreatic artery. Abbreviation: MSC, mesenchymal stem cell
FIGURE 2

FIGURE 2

Characterization of autologous bone marrow‐derived…

FIGURE 2

Characterization of autologous bone marrow‐derived mesenchymal stem cells (BM‐MSCs) isolated from the control…

FIGURE 2 Characterization of autologous bone marrow‐derived mesenchymal stem cells (BM‐MSCs) isolated from the control group (group 1) and from patients with type 2 diabetes mellitus (T2DM) (duration of T2DM: group 2: 10 years). A, Typical morphology of BM‐MSCs cultured under xeno‐ and serum‐free culture conditions. These cells were plastic‐adherent, spindle‐shaped, and fibroblast‐like. B, The population doubling time (hours) of BM‐MSCs indicated a significant difference in the growth rates of groups 3 and 4 compared with those of group 1 (control group) and group 2. C, The flow cytometry analysis of mesenchymal stem cell surface markers, including the positive markers CD73, CD90, and CD105, and the absence of hematopoietic markers (CD34, CD45, CD14 or CD11b, CD79α or CD19, and HLA‐DR) confirmed that all BM‐MSCs expressed more than 95% of positive markers and less than 2% of negative markers. D, A normal karyotype was maintained in all cells cultured under xeno‐ and serum‐free conditions. E, All BM‐MSCs from the four groups were able to differentiate into adipocytes, chondrocytes, and osteoblasts. Scale bar: 100 μm. APC, allophycocyanin; Cy5.5, cyanine dyes 5.5; FITC, fluorescein isothiocyanate; HLA‐DR, human leukocyte antigen ‐ DR isotype; PE, phycoerythrin; PerCP, peridinin chlorophyll protein complex; *P<.05; **P<0.01; ***P<0.001
FIGURE 3

FIGURE 3

Metabolic profiles of bone marrow‐derived…

FIGURE 3

Metabolic profiles of bone marrow‐derived mesenchymal stem cells (BM‐MSCs) isolated from the control…

FIGURE 3 Metabolic profiles of bone marrow‐derived mesenchymal stem cells (BM‐MSCs) isolated from the control group and from patients with type 2 diabetes mellitus (T2DM). A, Phenotype analysis of the OCR (pmol/minute per cell) and ECAR (mpH/minute per cell) using the Seahorse XF Cell Energy Phenotype Test. B, Metabolic potential ([stressed OCR or ECAR ÷ baseline OCR or ECAR] × 100%) between samples from normal individuals and patients with T2DM. C, Profiles of mitochondrial respiration assessed using the Seahorse XF Cell Mito Stress Test. Arrows indicate injections of the specific stressors oligomycin, carbonyl cyanite‐4 phenylhydrazone, and rotenone/antimycin A into the assay medium. D, Calculated respiration values for the control and T2DM samples. E, Glycolysis profiles of BM‐MSCs obtained using the Seahorse XF Glycolysis Stress Test Kit; arrows indicate the injection of glucose, oligomycin, and 2‐deoxyglucose into the assay medium. F, Calculated glycolysis rate, glycolytic capacity, and glycolytic reserves of BM‐MSCs isolated from the control group and the T2DM groups. 2‐DG, 2‐deoxyglucose; ECAR, extracellular acidification rate; FCCP, carbonyl cyanite‐4 phenylhydrazone; Glu, glucose; OCR, oxygen consumption rate; Olig, oligomycin; Rot., rotenone/antimycin A. * P<.05
FIGURE 4

FIGURE 4

Characterization of mitochondrial DNA (mtDNA)…

FIGURE 4

Characterization of mitochondrial DNA (mtDNA) isolated from bone marrow‐derived mesenchymal stem cells of…

FIGURE 4 Characterization of mitochondrial DNA (mtDNA) isolated from bone marrow‐derived mesenchymal stem cells of the control group (group 1) and patients with type 2 diabetes mellitus (T2DM) (duration of T2DM: group 2: 10 years). A,B, Number of mtDNA variants among the study groups, including homoplasmic variants (A) and heteroplasmic variants (B). C, Dynamics of the heteroplasmy level of several mtDNA variants across the study groups. The revised Cambridge Reference Sequence was applied as reference mitochondrial sequence. rCRS, revised Cambridge Reference Sequence
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