Type 2 Diabetes Inhibited Human Mesenchymal Stem Cells Angiogenic Response by Over‐Activity of the Autophagic Pathway

Rezabakhsh, Aysa; Cheraghi, Omid; Nourazarian, Alireza; Hassanpour, Mehdi; Kazemi, Mohammad Reza; Ghaderi, Shahrooz; Faraji, Esmaeil; Rahbarghazi‬, Reza; Avci, Çığır Biray; Bağca, Bakiye Göker; Garjani, Alireza

doi:10.1002/jcb.25814

Cited by 58 publications

(56 citation statements)

References 48 publications

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“…Another study of human mesenchymal stem cells indicated that, although diabetic sera induced autophagy at the early stage, it inhibited autophagy at a late stage. Inhibition of insulin on autophagy occurred through two mechanisms: by activating mTORC1 resulting in the inhibition of ULK1 and by activating protein kinase B, which inhibits FOXO3 [41,42].…”

Section: Discussionmentioning

confidence: 99%

High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

et al. 2017

Endocr J

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METABOLIC DISORDERS, such as PCOS (polycystic ovary syndrome) and T2DM (type 2 diabetes mellitus), are reported to be associated with high miscarriage rates, decreased pregnancy rates, and low live birth rates [1]. PCOS and T2DM are characterized by hyperinsulinemia [2]. PCOS is an endocrine and metabolic disorder with a prevalence ranging from 5 to 13% in women of reproductive age. Moreover, PCOS is often accompanied by menstrual dysfunction, anovulaHigh insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process Abstract. Metabolic disorders, such as PCOS (polycystic ovarian syndrome) and T2DM (type 2 diabetes mellitus), are associated with menstrual dysfunction, anovulation, infertility, and early pregnancy loss. Ovarian dysfunction is not only related to low pregnancy rates but also to the increased risk of miscarriage. Women with PCOS or T2DM, characterized by hyperinsulinemia, commonly experience ovarian dysfunction. In this study, we first explored whether high insulin levels directly affected ovarian functioning during embryo implantation. Mice in the insulin-treated group were given a subcutaneous injection of human recombinant insulin. After insulin treatment, serum levels of E2 (estrogen), PROG (progesterone), LH (luteinizing hormone), and FSH (follicle-stimulating hormone) were obviously lower, and there was a significant decrement of ovarian GDF9 (growth differentiation factor 9) mRNA. H&E (hematoxylin and eosin) staining showed a greater number of immature follicles and less luteinization in the insulin group. Further autophagy was studied in this process. A significant increase of P62 (SQSTM1/Sequestosome1) and a decrease of Cathepsin B, BECN1 (Beclin 1), and ULK1 (Unc-51-like kinase 1) mRNA in ovary was found in the insulin group. Western blot analysis showed that the expressions of LC3 (microtubule-associated protein 1 light chain 3), BECN1, and Cathepsin B proteins in ovaries from insulin group were obviously reduced, while P62 proteins were significantly increased. All these results illustrated that insulin could directly impair ovarian function during embryo implantation and the imbalance of ovarian autophagy due to insulin. Autophagy could enhance the impaired ovarian function results from insulin.

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Section: Discussionmentioning

confidence: 99%

High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

et al. 2017

Endocr J

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“…It has been reported that DM2 has adverse effects on MSCs function, inhibiting the angiogenic ability of MSCs through the downregulation of pro‐angiogenic factors. Furthermore, BM‐MSCs from diabetic patients show hampered paracrine secretion and an increased propensity to differentiate into adipocytes .…”

Section: Msc Donor‐related Variability Mattersmentioning

confidence: 99%

Challenges in Clinical Development of Mesenchymal Stromal/Stem Cells: Concise Review

Mastrolia

Foppiani

Murgia

et al. 2019

Stem Cells Translational Medicine

235

182

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Summary Identified 50 years ago, mesenchymal stromal/stem cells (MSCs) immediately generated a substantial interest among the scientific community because of their differentiation plasticity and hematopoietic supportive function. Early investigations provided evidence of a relatively low engraftment rate and a transient benefit for challenging congenital and acquired diseases. The reasons for these poor therapeutic benefits forced the entire field to reconsider MSC mechanisms of action together with their ex vivo manipulation procedures. This phase resulted in advances in MSCs processing and the hypothesis that MSC‐tissue supportive functions may be prevailing their differentiation plasticity, broadening the spectrum of MSCs therapeutic potential far beyond their lineage‐restricted commitments. Consequently, an increasing number of studies have been conducted for a variety of clinical indications, revealing additional challenges and suggesting that MSCs are still lagging behind for a solid clinical translation. For this reason, our aim was to dissect the current challenges in the development of still promising cell types that, after more than half a century, still need to reach their maturity. Stem Cells Translational Medicine 2019;8:1135–1148

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“…Consistent with our results, the transdifferentiation of diabetic CPCs to vascular cells such as ECs and pericytes and mature cardiomyocytes were inhibited after incubation with HGC which coincided with the down‐regulation of vWF, CD31, α‐SMA, NG 2 , and cTnT both in vitro and in vivo. Previously, Rezabakhsh and co‐workers found a decreased mesenchymal stem cell to EC differentiation under diabetic condition governed by an abnormal activity of autophagy marker P62 . In addition to reduced CPC differentiation into EC, no lipoprotein lipase activity was scored in CPCs subjected to medium with 30mM glucose.…”

Section: Discussionmentioning

confidence: 95%

High glucose condition limited the angiogenic/cardiogenic capacity of murine cardiac progenitor cells in in vitro and in vivo milieu

Khaksar

Sayyari

Rezaie

et al. 2018

Cell Biochemistry & Function

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Murine c-kit cardiac cells were isolated and enriched by magnetic activated cell sorting technique. c-kit cells viability and colony-forming activity were evaluated by MTT and clonogenic assay. c-kit cells were exposed to endothelial, pericyte, and cardiomyocyte induction media containing 30mM glucose for 7 days. We monitored the level of endothelial (VE-cadherin, CD31, and vWF), pericyte (NG , α-SMA, and PDGFR-β), and cardiomyocyte markers (cTnT) using flow cytometry, real-time Polymerase Chain Reaction (PCR), and Enzyme-Linked Immunosorbent Assay (ELISA) analyses. Ultrastructural changes were studied by transmission electron microscopy (TEM) in cells treated with 5-Azacytidine and 30mM glucose. Matrigel plug assay was performed to determine the angio/cardiogenic property of c-kit cells in a diabetic mouse model. Glucose of 30mM decreased c-kit cells viability and clonogenicity (P < 0.05). The transdifferentiation capacity of c-kit cells into the endothelial lineage, pericytes, and cardiomyocytes were reduced through the inhibition of related genes (P < 0.05). TEM analysis revealed cardiomyocyte differentiation rate in c-kit cells coincided with an increased intracellular lipid accumulation and reduced number of mitochondria. Similar to in vitro condition, the angiogenic capacity of c-kit cells was aborted in vivo indicated by reduced NG , α-SMA, CD31, and vWF levels. High glucose condition reduces the angio/cardiogenic capacity of cardiac c-kit cells in vitro and in vivo. SIGNIFICANCE OF THE STUDY: High glucose condition seen in diabetes mellitus could affect the regenerative potential of cardiac tissue. The current experiment showed that the exposure of murine cardiac progenitor cells (CD117 cells) to condition containing 30mM glucose could decrease the differentiation properties into endothelial cells, pericytes, and mature cardiomyocytes in vitro and in vivo. Our finding confirmed that the angiogenic/cardiogenic potential cardiac progenitor cells decrease under treatment with high glucose content as seen in the diabetic condition.

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Type 2 Diabetes Inhibited Human Mesenchymal Stem Cells Angiogenic Response by Over‐Activity of the Autophagic Pathway

Cited by 58 publications

References 48 publications

High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

Challenges in Clinical Development of Mesenchymal Stromal/Stem Cells: Concise Review

High glucose condition limited the angiogenic/cardiogenic capacity of murine cardiac progenitor cells in in vitro and in vivo milieu

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