Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

Dai, Chunhua; Hang, Yan; Shostak, Alena; Poffenberger, Greg; Hart, Nathaniel; Prasad, Nripesh; Phillips, Neil; Levy, Shawn; Greiner, Dale L.; Shultz, Leonard D.; Bottino, Rita; Kim, Seung K.; Powers, Alvin C.

doi:10.1172/jci91761

Cited by 122 publications

(128 citation statements)

References 63 publications

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“…This provides the first concrete molecular target to manipulate human β-cell proliferation 94–96 . In addition, other pathways involved in human β-cell proliferation, such as calcineurin and SerpinB1, are being identifed 97,98 . To advance these reagents into clinics will require controlling the cell type specificity, targeting the intervention to islets, and ensuring that reagents that impinge on conserved cell cycle machineries do not raise the problem of tumour formation.…”

Section: Strategies To Produce New Endocrine Islet Cellsmentioning

confidence: 99%

Pancreas regeneration

Zhou¹,

Melton²

2018

Nature

275

184

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The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic hormone insulin. Human islets possess limited regenerative ability; loss of islet β-cells in diseases such as type 1 diabetes requires therapeutic intervention. The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration.

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Section: Strategies To Produce New Endocrine Islet Cellsmentioning

confidence: 99%

Pancreas regeneration

Zhou¹,

Melton²

2018

Nature

275

184

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“…We found that genes with the highest cell type-specific expression were those linked to multiple DORs in the same cluster (Figure 3B). For example, we observed two distinct β-cell DORs near GLP1R, which encodes a G protein-coupled receptor expressed in human β-cells but not in α-cells, ducts or acinar cells (Dai et al, 2017). For DACH2, which encodes a transcription factor expressed in human β-cells, we detected five distinct DORs.…”

Section: Resultsmentioning

confidence: 99%

A Chromatin Basis for Cell Lineage and Disease Risk in the Human Pancreas

et al. 2018

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Understanding the genomic logic that underlies cellular diversity and developmental potential in the human pancreas will accelerate the growth of cell replacement therapies and reveal genetic risk mechanisms in diabetes. Here, we identified and characterized thousands of chromatin regions governing cell-specific gene regulation in human pancreatic endocrine and exocrine lineages, including islet β cells, α cells, duct, and acinar cells. Our findings have captured cellular ontogenies at the chromatin level, identified lineage-specific regulators potentially acting on these sites, and uncovered hallmarks of regulatory plasticity between cell types that suggest mechanisms to regenerate β cells from pancreatic endocrine or exocrine cells. Our work shows that disease risk variants related to pancreas are significantly enriched in these regulatory regions and reveals previously unrecognized links between endocrine and exocrine pancreas in diabetes risk.

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“…Finally, since the highest rates of human beta cell proliferation in vivo are observed in juvenile beta cells and human insulinomas, we and others have used these cell types as data mines for human beta cell replication [39,54]. …”

Section: Drug Discovery Strategiesmentioning

confidence: 99%

Advances in drug discovery for human beta cell regeneration

et al. 2018

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The numbers of insulin-secreting pancreatic beta cells are reduced in people with type 1 and type 2 diabetes. Driving beta cell regeneration in the pancreases of people with diabetes would be an attractive approach to reversing diabetes. While adult human beta cells have long been believed to be terminally differentiated and, therefore, irreversibly quiescent, it has become clear over recent years that this is not true. More specifically, both candidate and unbiased high-throughput screen approaches have revealed several classes of molecules that are clearly able to induce human beta cell proliferation. Here, we review recent approaches and accomplishments in human beta cell regenerative drug discovery. We also list the challenges that this rapidly moving field must confront to translate beta cell regenerative therapy from the laboratory to the clinic.

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Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

Cited by 122 publications

References 63 publications

Pancreas regeneration

Pancreas regeneration

A Chromatin Basis for Cell Lineage and Disease Risk in the Human Pancreas

Advances in drug discovery for human beta cell regeneration

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