Sonic hedgehog pathway suppression and reactivation accelerates differentiation of rat adipose-derived mesenchymal stromal cells toward insulin-producing cells

Dayer, Dian; Tabar, Mahmoud Hashemi; Moghimipour, Eskandar; Tabandeh, Mohammad Reza; Ghadiri, Ataallah; Bakhshi, Elham Allah; Orazizadeh, Mahmoud; Ghafari, M

doi:10.1016/j.jcyt.2017.05.003

Cited by 28 publications

(26 citation statements)

References 25 publications

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“…The induction of ADSC-derived IPCs may be due to the activation of the islet cell development-related genes in IPCs. The expressions of PDX1, 54 Ngn3, 53 NeuroD, 55 and Insulin 56 mRNA were in line with the results of previous studies, indicating that the ADSCs had differentiated toward IPCs. The interaction of PDX1, Ngn3 and V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) activated mouse insulin promoter to trans-differentiate pancreatic and exocrine cells into insulin-producing beta-like cells.…”

Section: Discussionsupporting

confidence: 90%

“…49,50 After comparing the expression of endogenous Cdc42 protein in ADSCs and rat islets, in accordance with previous studies, we successfully induce ADSCs into IPCs. [51][52][53] Our data indicate that high glucose (4.5 g/L D-glucose) and DMSO (10%) significantly promote the induction of IPCs from ADSCs. Interestingly, after we constructed DTZ staining to further verify the induction of IPCs, some cells in the control group fell off, but the induction group remained.…”

Section: Discussionmentioning

confidence: 99%

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<p>Cdc42 Promotes ADSC-Derived IPC Induction, Proliferation, And Insulin Secretion Via Wnt/β-Catenin Signaling</p>

Xiao

Huang

Qian

et al. 2019

DMSO

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Type 1 diabetes mellitus (T1DM) is characterized by irreversible islet β cell destruction. Accumulative evidence indicated that Cdc42 and Wnt/β-catenin signaling both play a critical role in the pathogenesis and development of T1DM. Further, bio-molecular mechanisms in adipose-derived mesenchymal stem cells (ADSCs)-derived insulin-producing cells (IPCs) remain largely unknown. Our aim was to investigate the underlying mechanism of Cdc42/Wnt/β-catenin pathway in ADSC-derived IPCs, which may provide new insights into the therapeutic strategy for T1DM patients. Methods: ADSC induction was accomplished with DMSO under high-glucose condition. ML141 (Cdc42 inhibitor) and Wnt-3a (Wnt signaling activator) were administered to ADSCs from day 2 until the induction finished. Morphological changes were determined by an inverted microscope. Dithizone staining was employed to evaluate the induction of ADSCderived IPCs. qPCR and Western blotting were employed to measure the mRNA and protein expression level of islet cell development-related genes and Wnt signaling-related genes. The proliferation ability of ADSC-derived IPCs was also detected with a cell counting kit (CCK) assay. The expression and secretion of Insulin were detected with immunofluorescence test and enzyme-linked immunosorbent assay (ELISA) respectively. Results: During induction, morphological characters of ADSCs changed into spindle and round shape, and formed islet-line cell clusters, with brown dithizone-stained cytoplasm. Expression levels of islet cell development-related genes were up-regulated in ADSCderived IPCs. Wnt-3a promoted Wnt signaling markers and islet cell development-related gene expression at mRNA and protein levels, while ML141 played a negative effect. Wnt-3a promoted ADSC-derived IPC proliferation and glucose-stimulated insulin secretion (GSIS), while ML141 played a negative effect. Conclusion: Our research demonstrated that DMSO and high-glucose condition can induce ADSCs into IPCs, and Wnt signaling promotes the induction. Cdc42 may promote IPC induction, IPC proliferation and insulin secretion via Wnt/β-catenin pathway, meaning that Cdc42 may be regarded as a potential target in the treatment of T1DM.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

<p>Cdc42 Promotes ADSC-Derived IPC Induction, Proliferation, And Insulin Secretion Via Wnt/β-Catenin Signaling</p>

Xiao

Huang

Qian

et al. 2019

DMSO

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“…However, hAdScs and hAMScs cannot differentiate into IPcs through the suppression of NRSF alone. Although SHH is not normally expressed in the pancreatic domain, a study reported that SHH is required for the initiation of pancreas gene expression in the posterior foregut (25). consistently, hAdScs and hAMScs cannot differentiate into IPcs via suppression of SHH alone.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, sonic hedgehog (SHH) signaling exerts opposite roles in neuron and pancreas development. While the expression of SHH promotes neuronal development (25), it also inhibits pancreas specification (26,27).…”

Section: The Differentiation Of Human Mscs Derived From Adipose and Amentioning

confidence: 99%

The differentiation of human MSCs derived from adipose and amniotic tissues into insulin-producing cells, induced by PEI@Fe3O4 nanoparticles-mediated NRSF and SHH silencing

Wang

Zhang

et al. 2018

Int J Mol Med

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Type 1 diabetes involves the immunologically mediated destruction of insulin‑producing cells (IPCs) in the pancreatic islet. Mesenchymal stem cells (MSCs) have the ability to differentiate into IPCs and have become the most promising means for diabetes therapy. The present study demonstrated that human adipose‑derived stem cells (hADSCs) and human amniotic MSCs (hAMSCs) are able to differentiate into functional IPCs by knocking down neuronal restrictive silencing factor (NRSF) and Sonic hedgehog (SHH). In the current study, PEI@Fe3O4 nanoparticles (NPs) were used to deliver NRSF small interfering (si)RNA and SHH siRNA to hADSCs and hAMSCs. Following infection with PEI@Fe3O4 NPs containing NRSF siRNA and SHH siRNA, the MSCs were induced to differentiate into IPCs. Four specific genes for islet cells were expressed in the differentiated cells. These cells also produced and released insulin in a glucose‑responsive manner. These findings indicated that hADSCs and hAMSCs may be induced to differentiate into IPCs via PEI@Fe3O4 NP‑mediated NRSF and SHH silencing.

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“…Relative quantification was performed according to the comparative 2 − ΔΔCt method and using Lightcycler 96 ® software. Validation of assays to check that the primer for the target genes and GAPDH had similar amplification efficiencies was performed as described previously [18]. All qPCR analysis was performed according to the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guideline [11].…”

Section: Gene Expression Analysis Of Neurotrophic Factorsmentioning

confidence: 99%

Effects of Two Training Programs on Transcriptional Levels of Neurotrophins and Glial Cells Population in Hippocampus of Experimental Multiple Sclerosis

et al. 2018

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The aim of the present study was to investigate the effects of high-intensity interval training (HIIT) versus low-intensity continuous training (LICT) on transcriptional levels of neurotrophic factors and oligodendrocyte/microglia cell loss in a cuprizone (CP) induced animal model of demyelination. Male C57BL/6 mice were assigned to six groups: control (C), cuprizone-induced demyelination (CP), interval training (IT), continuous training (CT), IT plus CP (ITCP), and CT plus CP (CTCP). Training programs on the treadmill were performed for four weeks, and then demyelination was induced by feeding mice a diet containing 0.2% cuprizone for five weeks. Animals that received cuprizone showed poorer motor function, lower expression of BDNF, GDNF, NGF, and fewer oligodendrocytes in the hippocampus compared to the control animals. The numbers of oligodendrocyte and microglia cells increased in the ITCP group compared to the CTCP group (P<0.05). Both training programs increased the mRNA levels of BDNF, GDNF and NGF, and the HIIT program was more effective than the LICT program (P<0.05). Both exercise programs prevented the abnormal neurological movements induced by cuprizone. Our results indicated that HIIT versus LICT had a greater neuroprotective effect against multiple sclerosis by improving gene expression for abnormal neurotrophins and cellular loss in the hippocampus.

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Sonic hedgehog pathway suppression and reactivation accelerates differentiation of rat adipose-derived mesenchymal stromal cells toward insulin-producing cells

Cited by 28 publications

References 25 publications

<p>Cdc42 Promotes ADSC-Derived IPC Induction, Proliferation, And Insulin Secretion Via Wnt/β-Catenin Signaling</p>

<p>Cdc42 Promotes ADSC-Derived IPC Induction, Proliferation, And Insulin Secretion Via Wnt/β-Catenin Signaling</p>

The differentiation of human MSCs derived from adipose and amniotic tissues into insulin-producing cells, induced by PEI@Fe3O4 nanoparticles-mediated NRSF and SHH silencing

Effects of Two Training Programs on Transcriptional Levels of Neurotrophins and Glial Cells Population in Hippocampus of Experimental Multiple Sclerosis

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