| First Author | Dadheech N | Year | 2022 |
| Journal | Sci Rep | Volume | 12 |
| Issue | 1 | Pages | 21496 |
| PubMed ID | 36513699 | Mgi Jnum | J:334784 |
| Mgi Id | MGI:7410505 | Doi | 10.1038/s41598-022-25405-w |
| Citation | Dadheech N, et al. (2022) Role of poly(ADP-ribose) polymerase-1 in regulating human islet cell differentiation. Sci Rep 12(1):21496 |
| abstractText | Poly(ADP-ribose) polymerase-1 (PARP1), a fundamental DNA repair enzyme, is known to regulate beta cell death, replication, and insulin secretion. PARP1 knockout (KO) mice are resistant to diabetes, while PARP1 overactivation contributes to beta cell death. Additionally, PARP1 inhibition (PARPi) improves diabetes complications in patients with type-2 diabetes. Despite these beneficial effects, the use of PARP1 modulating agents in diabetes treatment is largely neglected, primarily due to the poorly studied mechanistic action of PARP1 catalytic function in human beta cell development. In the present study, we evaluated PARP1 regulatory action in human beta cell differentiation using the human pancreatic progenitor cell line, PANC-1. We surveyed islet census and histology from PARP1 wild-type versus KO mice pancreas in a head-to-head comparison with PARP1 regulatory action for in-vitro beta cell differentiation following either PARP1 depletion or its pharmacological inhibition in PANC-1-differentiated islet cells. shRNA mediated PARP1 depleted (SiP) and shRNA control (U6) PANC-1 cells were differentiated into islet-like clusters using established protocols. We observed complete abrogation of new beta cell formation with absolute PARP1 depletion while its inhibition using the potent inhibitor, PJ34, promoted the endocrine beta cell differentiation and maturation. Immunohistochemistry and immunoblotting for key endocrine differentiation players along with beta cell maturation markers highlighted the potential regulatory action of PARP1 and augmented beta cell differentiation due to direct interaction of unmodified PARP1 protein elicited p38 MAPK phosphorylation and Neurogenin-3 (Ngn3) re-activation. In summary, our study suggests that PARP1 is required for the proper development and differentiation of human islets. Selective inhibition with PARPi can be an advantage in pushing more insulin-producing cells under pathological conditions and delivers a potential for pilot clinical testing for beta cell replacement cell therapies for diabetes. |
