Administration of Tonsil-Derived Mesenchymal Stem Cells Improves Glucose Tolerance in High Fat Diet-Induced Diabetic Mice via Insulin-Like Growth Factor-Binding Protein 5-Mediated Endoplasmic Reticulum Stress Modulation

Abstract

Type 2 diabetes mellitus (T2DM) is a prevalent chronic metabolic disorder accompanied by high blood glucose, insulin resistance, and relative insulin deficiency. Endoplasmic reticulum (ER) stress induced by high glucose and free fatty acids has been suggested as one of the main causes of β-cell dysfunction and death in T2DM. Stem cell-derived insulin-secreting cells were recently suggested as a novel therapy for diabetes. In the present study, we demonstrate the therapeutic potential of tonsil-derived mesenchymal stem cells (TMSCs) to treat high-fat diet (HFD)-induced T2DM. To explore whether TMSC administration can alleviate T2DM, TMSCs were intraperitoneally injected in HFD-induced T2DM mice once every 2 weeks. TMSC injection markedly improved glucose tolerance and glucose-stimulated insulin secretion and prevented HFD-induced pancreatic β-cell hypertrophy and cell death. In addition, TMSC injection relieved the ER-stress response and preserved gene expression related to glucose sensing and insulin secretion. Moreover, administration of TMSC-derived conditioned medium induced similar therapeutic outcomes, suggesting paracrine effects. Finally, proteomic analysis revealed high secretion of insulin-like growth factor-binding protein 5 by TMSCs, and its expression was critical for the protective effects of TMSCs against HFD-induced glucose intolerance and ER-stress response in pancreatic islets. TMSC administration can alleviate HFD-induced-T2DM via preserving pancreatic islets and their function. These results provide novel evidence of TMSCs as an ER-stress modulator that may be a novel, alternative cell therapy for T2DM.

Adipose-Derived Stem Cells Protect Ischemia-Reperfusion and Partial Hepatectomy by Attenuating Endoplasmic Reticulum Stress

“…In our study, CHOP and p-JNK were significantly elevated after IRI, indicating that both pathways are activated in the IR porcine liver due to excessive ERS. Consistent with the findings of Lee et al (2019) that tonsilderived MSCs have an inhibitory effect on CHOP, we found that the ADSCs also downregulated this protein in the injured liver. Thus, ADSCs can alleviate hepatic IRI damage by reducing ERS-induced apoptosis as well.…”

The Role of Oxymatrine in Amelioration of Acute Lung Injury Subjected to Myocardial I/R by Inhibiting Endoplasmic Reticulum Stress in Diabetic Rats

“…Diabetes is characterized by persistent hyperglycemia, which may lead to diverse representative complications including cardiomyopathy, nephropathy, diabetic foot, and diabetic neuropathy, which significantly contribute to the associated rates of morbidity and mortality [ 2 ]. Additionally, diabetes may accelerate the deterioration of respiratory function with characteristic anatomical and biological changes to the diabetic lung [ 5 , 23 , 24 ]. These abnormalities affect lung volume, pulmonary diffusing capacity, ventilation control, bronchomotor tone, and neuroadrenergic bronchial innervation.…”

“…Acute myocardial infarction is associated with higher mortality rates in patients with diabetes [ 3 ]. Diabetes also increases susceptibility myocardial ischemia/reperfusion (I/R) injury, which can induce endoplasmic reticulum stress (ERS) [ 4 , 5 ]. ERS refers to ischemia, hypoxia, oxidative stress, and glucose/nutrition abnormalities where material deficiencies promote abnormal glycosylation reactions and calcium ion homeostasis, significantly increasing the number of unfolded proteins in the ER.…”

Tonsil-derived mesenchymal stem cells enhance allogeneic bone marrow engraftment via collagen IV degradation

“…The conditioned media of various MSCs were obtained, as previously reported with a few modifications [18]. Cells at 80% confluence were washed twice with PBS and incubated in serum-free DMEM for 48 h. The conditioned media were collected, filtered by centrifugation at 190 × g at room temperature for 5 min to remove suspended cells and concentrated using an Amicon Ultra Centrifugal Filter unit (molecular weight cut-off value of 3KDa; Merck, Darmstadt, Germany) by high-speed centrifugation at 5000 × g at 4°C for 1 h. Nano-liquid chromatography coupled with tandem mass spectrometry (nano LC-MS/MS) analysis using the Mascot algorithm (Matrix Science, Boston, MA, USA) was performed, as previously reported [13].…”

“…Our research group has been investigating therapeutic effects of TMSCs and their mechanisms of action. By performing transcriptomic and proteomic analyses, we screened molecules with higher expression levels in TMSCs compared to bone marrow (BM) or adipose tissue (AD) MSCs [12,13]. Furthermore, we have reported immune modulating, anti-fibrotic, and insulin sensitizing effects of TMSCs via secreting PD-L1, IL-1Ra, and IGFBP5, respectively [13][14][15].…”