BMP-7 Induces Adult Human Pancreatic Exocrine-to-Endocrine Conversion

Klein, Dagmar; Álvarez-Cubela, Silvia; Lanzoni, Giacomo; Vargas, Nancy; Prabakar, Kamalaveni R.; Boulina, Maria; Ricordi, Camillo; Inverardi, Luca; Pastori, Ricardo L.; Domínguez‐Bendala, Juan

doi:10.2337/db15-0688

Cited by 54 publications

(53 citation statements)

References 52 publications

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“…Similarly, acinar cells with also glucagon granules have been described in two individuals with type 1 diabetes [16]. In agreement with these latter findings, work from a few laboratories has demonstrated ex vivo formation of beta cell like cells from human acinar tissue by the use of different experimental approaches [17,18]. However, clues are missing on whether this may be the case in vivo in the human T2D condition.…”

Section: Introductionmentioning

confidence: 62%

Co-localization of acinar markers and insulin in pancreatic cells of subjects with type 2 diabetes

et al. 2017

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To search for clues suggesting that beta cells may generate by transdifferentiation in humans, we assessed the presence of cells double positive for exocrine (amylase, carboxypeptidase A) and endocrine (insulin) markers in the pancreas of non-diabetic individuals (ND) and patients with type 2 diabetes (T2D). Samples from twelve ND and twelve matched T2D multiorgan donors were studied by electron microscopy, including amylase and insulin immunogold labeling; carboxypeptidase A immunofluorescence light microscopy assessment was also performed. In the pancreas from four T2D donors, cells containing both zymogen-like and insulin-like granules were observed, scattered in the exocrine compartment. Nature of granules was confirmed by immunogold labeling for amylase and insulin. Double positive cells ranged from 0.82 to 1.74 per mm2, corresponding to 0.26±0.045% of the counted exocrine cells. Intriguingly, cells of the innate immune systems (mast cells and/or macrophages) were adjacent to 33.3±13.6% of these hybrid cells. No cells showing co-localization of amylase and insulin were found in ND samples by electron microscopy. Similarly, cells containing both carboxypeptidase A and insulin were more frequently observed in the diabetic pancreata. These results demonstrate more abundant presence of cells containing both acinar markers and insulin in the pancreas of T2D subjects, which suggests possible conversion from one cellular type to the other and specific association with the diseased condition.

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Section: Introductionmentioning

confidence: 62%

Co-localization of acinar markers and insulin in pancreatic cells of subjects with type 2 diabetes

et al. 2017

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“…Given that systemic noggin treatment improves glucose homeostasis in type 2 diabetic mice, there may be several targets adding to this effect [114]. In addition, it has recently been shown that transient stimulation of human pancreatic exocrine tissue with BMP4 or 7 results in differentiation of exocrine cells into insulin producing cells following removal of the BMP stimulus [121]. If this holds true it may explain some of the divergences between in vitro and in vivo findings.…”

Section: Effect Of Bmps On Glucose Homeostasis and Pancreatic Islet Fmentioning

confidence: 96%

Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism

Grgurević

Christensen

Schulz

et al. 2016

Cytokine & Growth Factor Reviews

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“…How these cells participate in the endocrine reprogramming potential of the exocrine compartment is unclear since in vitro studies involved ipso facto unselected tissues. A recent study by Klein and colleagues using cultures of human islet-depleted exocrine tissue showed that acinar (elastase 3a + ) and ductal (CAII + ) cells participated poorly to bone morphogenetic 7-induced endocrine reprogramming [Klein et al 2015]. Instead, cells expressing PDX1 at the time of lentiviral-based tagging participated to almost 50% of the C-peptide + cells retrieved after differentiation protocols.…”

Section: In Vitro Reprogramming Of Pancreatic Ductal Cells Into β Cellsmentioning

confidence: 99%

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

Corritore

Lee

Sokal

et al. 2016

Therapeutic Advances in Endocrinology

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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.

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BMP-7 Induces Adult Human Pancreatic Exocrine-to-Endocrine Conversion

Cited by 54 publications

References 52 publications

Co-localization of acinar markers and insulin in pancreatic cells of subjects with type 2 diabetes

Co-localization of acinar markers and insulin in pancreatic cells of subjects with type 2 diabetes

Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism

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

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