Direct lineage tracing reveals Activin-a potential for improved pancreatic homing of bone marrow mesenchymal stem cells and efficient ß-cell regeneration in vivo

Dadheech, Nidheesh; Srivastava, Abhay; Vakani, Mitul; Shrimali, Paresh; Bhonde, Ramesh; Gupta, Sarita

doi:10.1186/s13287-020-01843-z

Cited by 16 publications

(14 citation statements)

References 39 publications

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“…Université Laval, Quebec, Canada) and maintained in high glucose DMEM supplemented with 10% Fetal Bovine Serum. PANC-1 cells were allowed for differentiation in presence of activin-A using 20ng/ml dose as previously described 25,26 . After differentiation, islet-like clusters were tested for the presence of insulin with Dithizone (DTZ) staining.…”

Section: Methodsmentioning

confidence: 99%

“…Differentiation into islet like clusters: Normal PANC-1 cells were differentiated using activin-A (20ng/m)l as differentiating factors in eight-day differentiation protocol described by Dadheech et al 25 . In order to better comprehend the differentiation procedure of islet neogenesis, differentiation of PANC-1, in presence and absence of PJ-34 (Inhibitor of PARP activity) at a concentration of 10μM.…”

Section: Methodsmentioning

confidence: 99%

“…For this, we performed de ned islet cell differentiation of human pancreatic progenitor cells, PANC-1 into islet-like aggregates using established methods and tested growth factor, activin-A, a TGF-β ligand. Human Pancreatic carcinoma cells, PANC-1 has been shown to inherit pancreatic stem/progenitor-like properties and previously been documented for islet differentiation using activin-A [24][25][26] . Brie y, PANC-1 cells were treated with activin-A in de ned media and stage-speci c differentiation.…”

Section: Parp-1 Depletion Impairs Human Islet Development and Differe...mentioning

confidence: 99%

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Catalytic-independent function of PARP-1 is essential in regulating human islet-cell differentiation from stem cells

Dadheech

Srivast

Shah

et al. 2022

Preprint

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Poly (ADP) Ribose Polymerase-1 (PARP-1), a fundamental DNA repair enzyme is known to regulate β cell death, replication, and insulin secretion. PARP-1 knockout (KO) mice are resistant to diabetes while PARP-1 overactivation contributes to β cell death. Additionally, PARP-1 inhibition improves diabetes complications in patients with type-2 diabetes. Despite these beneficial effects, the use of PARP-1 modulating agents in diabetes treatment are largely neglected, primarily due to the poorly studied mechanistic action of PARP-1 catalytic function in human β cell development. In the present study, we evaluated PARP-1 regulatory action in human β cell differentiation using the human pancreatic stem cell line, PANC-1. We surveyed islet census and histology from PARP-1 wild-type versus KO mice pancreas in head-to-head comparison with PARP-1 regulatory action for in-vitro β cell differentiation following either PARP-1 depletion or its pharmacological inhibition in PANC-1-differentiated islet cells. shRNA mediated PARP-1 depleted (SiP), or control replete (U6) PANC-1 cells were differentiated into islet-like clusters using established protocols. We observed complete abrogation of new β cell formation with absolute PARP-1 depletion while its catalytic inactivation using the strong inhibitor, PJ34, promoted the endocrine β cell differentiation and maturation. Immunohistochemistry and proteomics for key endocrine differentiation factors in addition to β cell maturation markers highlighted potential regulatory and augmented β cell differentiation due to non-catalytic function of PARP-1 elicited p-38 MAPK phosphorylation and Neurogenin-3 (Ngn3) re-activation. In summary, the study reestablishes a novel ability of catalytic independent action of PARP-1 in regulating islet cell differentiation and potential avenues for pilot clinical testing of PARP-1 inhibitors for β cell replacement therapies for the treatment of diabetes.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Parp-1 Depletion Impairs Human Islet Development and Differe...mentioning

confidence: 99%

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Catalytic-independent function of PARP-1 is essential in regulating human islet-cell differentiation from stem cells

Dadheech

Srivast

Shah

et al. 2022

Preprint

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“…The clinical application of MSCs is motivated from in vitro cell culture and in vivo studies in animal models of numerous diseases with promising results [ 28 , 30 , 42 , 43 ]. BM-MSCs can differentiate into functional β-cells [ 3 , 44 ]; (Tables 1 , 2 ), but also only little if any transdifferentiation capacity of MSCs-to-β-cells [ 45 – 47 ] and no spontaneous cell–cell fusion [ 24 , 48 ] have been observed.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow mesenchymal stromal cells for diabetes therapy: touch, fuse, and fix?

et al. 2022

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Bone marrow mesenchymal stromal cells (BM-MSCs) have anti-inflammatory and pro-survival properties. Naturally, they do not express human leukocyte antigen class II surface antigens and have immunosuppressive capabilities. Together with their relatively easy accessibility and expansion, they are an attractive tool for organ support in transplantation and regenerative therapy. Autologous BM-MSC transplantation alone or together with transplanted islets improves β-cell function, graft survival, and glycemic control in diabetes. Albeit MSCs’ capacity to transdifferentiate into β-cell is limited, their protective effects are mediated mainly by paracrine mechanisms through BM-MSCs circulating through the body. Direct cell–cell contact and spontaneous fusion of BM-MSCs with injured cells, although at a very low rate, are further mechanisms of their supportive effect and for tissue regeneration. Diabetes is a disease of long-term chronic inflammation and cell therapy requires stable, highly functional cells. Several tools and protocols have been developed by mimicking natural fusion events to induce and accelerate fusion in vitro to promote β-cell-specific gene expression in fused cells. BM-MSC-islet fusion before transplantation may be a strategy for long-term islet survival and improved function. This review discusses the cell-protective and anti-inflammatory characteristics of BM-MSCs to boost highly functional insulin-producing cells in vitro and in vivo, and the efficacy of their fusion with β-cells as a path to promote β-cell regeneration.

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“…In the recent years, systemic administration of BMSCs to regulate the immune response and enhance endogenous regeneration is becoming a new treatment strategy in immune hyperactivity and tissue injury diseases [21][22][23]. Intravascular injection of BMSCs has been confirmed to be an effective treatment for autoimmune diseases [24][25], graft vs. host disease (GVHD) [26][27], vascular diseases and diabetes [28][29]. Hundreds of clinical trials of BMSC cell therapy are now being carried out world-wide [30][31][32].…”

Section: Introductionmentioning

confidence: 99%

BMSC cells alleviate liver injury induced by ulcerative colitis via repairing the intestinal-liver barrier and activating hepatocyte growth factor

Deng¹,

Zhang²,

Meng³

et al. 2021

Preprint

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Background: Ulcerative colitis (UC), belongs to inﬂammatory bowel diseases (IBD), frequently induces liver inflammation and injury. Previous studies have proved that bone marrow-derived mesenchymal stem cells (BMSCs) can suppress inflammation and improve intestinal mucosal injury in colitis, however, the eﬀects of BMSCs on colitis-induced liver injury and the underlying molecular mechanisms remain unclear. Here, we investigated the eﬀects and mechanisms of BMSCs in acute ulcerative colitis Balb/C mice, which were induced by 4 % dextran sodium sulphate (DSS). Methods: In this study, BMSCs derived from Balb/C mice were administrated by single intravenous injection with a dose of 5*10^7 cells/kg. And then, the effects and underlying molecular mechanisms were investigated. Firstly, degree of liver injury in colitis mice was evaluated by hepatic ALT, AST, ALP and TBIL levels, which were measured by speciﬁc determination kits, the levels of TNF-α, IL-6, IFNγ and LPS were examined by ELISA. Secondly, as the indicator of intestinal-liver barrier disorder, tight junction proteins were analyzed by western blot. Thirdly, the pathological changes in colon and liver were detected by H&E staining. At last, homing of BMSCs to lesion tissues was investigated by Immunofluorescence. Results: The results indicated that histopathological changes in model mice had been greatly alleviated, BMSCs infusion remarkably decreased the serum ALT, AST, ALP and TBIL level, and meanwhile reduced pro-inflammatory cytokines in liver tissues. Furthermore, homing of BMSCs was observed in colon and liver, and the disorder of intestinal-liver barrier was declined significantly. Conclusions: In conclusion, BMSCs alleviate liver injury induced by ulcerative colitis via repairing the intestinal-liver barrier and activating hepatocyte growth factor, it has potential application prospects in the treatment of liver injury induced by ulcerative colitis.

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Direct lineage tracing reveals Activin-a potential for improved pancreatic homing of bone marrow mesenchymal stem cells and efficient ß-cell regeneration in vivo

Cited by 16 publications

References 39 publications

Catalytic-independent function of PARP-1 is essential in regulating human islet-cell differentiation from stem cells

Catalytic-independent function of PARP-1 is essential in regulating human islet-cell differentiation from stem cells

Bone marrow mesenchymal stromal cells for diabetes therapy: touch, fuse, and fix?

BMSC cells alleviate liver injury induced by ulcerative colitis via repairing the intestinal-liver barrier and activating hepatocyte growth factor

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