β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells

Abstract

Thorough research on the capacity of human islet transplantation to cure type 1 diabetes led to the achievement of 3-to 5-year-long insulin independence in nearly half of transplanted patients. Yet, translation of this technique to clinical routine is limited by organ shortage and the need for long-term immunosuppression, restricting its use to adults with unstable disease. The production of new bona fide β cells in vitro was thus investigated and finally achieved with human pluripotent stem cells (PSCs). Besides ethical concerns about the use of human embryos, studies are now evaluating the possibility of circumventing the spontaneous tumor formation associated with transplantation of PSCs. These issues fueled the search for cell candidates for β-cell engineering with safe profiles for clinical translation. In vivo studies revealed the regeneration capacity of the exocrine pancreas after injury that depends at least partially on facultative progenitors in the ductal compartment. These stimulated subpopulations of pancreatic ductal cells (PDCs) underwent β-cell transdifferentiation through reactivation of embryonic signaling pathways. In vitro models for expansion and differentiation of purified PDCs toward insulin-producing cells were described using cocktails of growth factors, extracellular-matrix proteins and transcription factor overexpression. In this review, we will describe the latest findings in pancreatic β-cell mass regeneration due to adult ductal progenitor cells. We will further describe recent advances in human PDC transdifferentiation to insulin-producing cells with potential for clinical translational studies.

Generation of insulin-secreting cells from mouse gallbladder stem cells by small molecules in vitro

“…Transplantation of mesenchymal stem cells was considered slowing the progression of diabetes and therefore allowing recovery of pancreatic cells. Also, β-like cells could be acquired from embryonic stem cell or induced pluripotent stem cells by stepwise differentiation [2, 3, 11, 29, 31–37]. Other studies demonstrated that cells from the liver, skin, etc.…”

Regenerating β cells of the pancreas – potential developments in diabetes treatment

“…It has been noted that budding of new islets from ductal epithelium is not only a feature of embryonic pancreatic development, but also happens during pancreatic regeneration following pancreatic injury in adults. Therefore, many efforts have been taken to regenerate β cells from cultured pancreatic ductal cells 38, 69, 71 . One of the first successful attempts comes from Ramiya et al , in which the authors have isolated ductal epithelial cells from non-obese diabetic (NOD) mice, cultured them in vitro , and differentiated them into islet-like structures 72 .…”

Gimmicks of gamma‐aminobutyric acid (GABA) in pancreatic β‐cell regeneration through transdifferentiation of pancreatic α‐ to β‐cells

“…The most promising way for curing diabetes is islet transplantation, mostly focused on T1DM patients (Kuise and Noguchi, 2011), but donor shortage and life‐long need for immunosuppressive drugs make it less feasible for a routine clinical procedure (Benthuysen et al, 2016). Given these difficulties, over the last three decades, various methods have been attempted to regenerate/replace functional β cells in diabetic patients (Corritore et al, 2016; Aguayo‐Mazzucato and Bonner‐Weir, 2018; Zhou and Melton, 2018; Ghani et al, 2019).…”