The Transplantation Resistance of Type II Diabetes Mellitus Adipose-Derived Stem Cells Is Due to G6PC and IGF1 Genes Related to the FoxO Signaling Pathway

Abstract

In cases of patients with rapidly progressive diabetes mellitus (DM), autologous stem cell transplantation is considered as one of the regenerative treatments. However, whether the effects of autonomous stem cell transplantation on DM patients are equivalent to transplantation of stem cells derived from healthy persons is unclear. This study revealed that adipose-derived mesenchymal stem cells (ADSC) derived from type II DM patients had lower transplantation efficiency, proliferation potency, and stemness than those derived from healthy persons, leading to a tendency to induce apoptotic cell death. To address this issue, we conducted a cyclopedic mRNA analysis using a next-generation sequencer and identified G6PC3 and IGF1, genes related to the FoxO signaling pathway, as the genes responsible for lower performance. Moreover, it was demonstrated that the lower transplantation efficiency of ADSCs derived from type II DM patients might be improved by knocking down both G6PC3 and IGF1 genes. This study clarified the difference in transplantation efficiency between ADSCs derived from type II DM patients and those derived from healthy persons and the genes responsible for the lower performance of the former. These results can provide a new strategy for stabilizing the quality of stem cells and improving the therapeutic effects of regenerative treatments on autonomous stem cell transplantation in patients with DM.

The circadian rhythms of mitochondrial function after transplantation of mesenchymal stem cells

“…In T2DM-ADSC, the expression of Emerin (a protein composing the nuclear membrane) was low, and the activity of mitochondrial enzymes was reduced 16 . We also demonstrated that the transplantation e ciency of T2DM-ADSC was lower than that of N-ADSC 19 . Subsequently, we performed an exhaustive mRNA analysis using next-generation sequencing and identi ed glucose-6-phosphatase catalytic subunit 3 (G6PC3) and insulin-like growth factor 1 (IGF1) as responsible genes for the difference in transplantation e ciency 19 .…”

AMFR and DCTN2 genes cause transplantation resistance of adipose-derived mesenchymal stem cells in type 1 diabetes mellitus

“…In T1DM ADSCs, the proliferative potential and stemness of the cells were reduced compared to normal ADSCs, which may affect their transplantation efficiency. We also reported reduced transplantation efficiency in immunodeficient mice with adipose-derived stem cells from type 2 diabetic patients (T2DM ADSCs); ( Horiguchi et al, 2021b ) however, exosome degeneration was not observed in T2DM ADSCs. This may suggest that the mechanism of reduced transplantation efficiency in T1DM ADSCs may be different than in type 2 diabetes.…”

“…We previously described that T1DM ADSCs show distinct cellular degeneration compared with stem cells derived from type 2 diabetes mellitus (T2DM), such as considerable spherical endoplasmic reticulum hypertrophy ( Horiguchi et al, 2021a ; Horiguchi et al, 2021b ; Horiguchi et al, 2021c ). In addition, our group has previously reported that exosomes from T1DM ADSCs are larger but fewer, and have a higher tetraspanin CD9-positive ratio ( Horiguchi et al, 2021a ).…”

Exosome Degeneration in Mesenchymal Stem Cells Derived from Patients with Type 1 Diabetes Mellitus

“…2021, 22, 10906 2 of 11 degeneration of nuclei and mitochondria and reduced adenosine triphosphate (ATP) activity in T2DM ADSCs [12]. Furthermore, we reported that T2DM ADSCs have low transplantation efficiency, proliferative capacity, and stemness, and are prone to apoptotic cell death [13]. Moreover, we identified the forkhead box protein O (FoxO) signaling pathwayrelated genes glucose 6 phosphatase 3 (G6PC3) and insulin-like growth factor 1 (IGF1) as the genes responsible for transplantation resistance through a comprehensive mRNA analysis using next-generation sequencing technology [13].…”

“…Furthermore, we reported that T2DM ADSCs have low transplantation 2 of 11 efficiency, proliferative capacity, and stemness, and are prone to apoptotic cell death [13]. Moreover, we identified the forkhead box protein O (FoxO) signaling pathway-related genes glucose 6 phosphatase 3 (G6PC3) and insulin-like growth factor 1 (IGF1) as the genes responsible for transplantation resistance through a comprehensive mRNA analysis using next-generation sequencing technology [13]. Furthermore, we demonstrated that G6PC3 and IGF1 double-knockdown improves the transplantation efficiency of T2DM ADSCs [13].…”