Identification of a LIF-Responsive, Replication-Competent Subpopulation of Human β Cells

Rosado-Olivieri, Edwin A.; Aigha, Idil I.; Kenty, Jennifer Hyoje-Ryu; Melton, Douglas A.

doi:10.1016/j.cmet.2019.12.009

Cited by 26 publications

(38 citation statements)

References 58 publications

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“…In addition, Lifr (LIF receptor) was only slightly expressed in clusters 2 and 10 (SFigure 11), the  cell subgroups that were exclusively from normal mice. However, Lifr expression was not detected in cluster 14 either, indicating that the highly proliferative subgroup of  cells identified in this study is not likely associated with LIF responsiveness, different from what was previously reported (42). In our study, we found that cluster 14 had high expression of Hmgb1 and Hmgb2 (SFigure 10), indicating that these two DNA binding proteins might initiate a transcriptional program that gives rises to the identity of this group of cells.…”

Section: Discussioncontrasting

confidence: 93%

Intermittent protein restriction improves glucose homeostasis and restores damaged islet beta cells in diabetic mice

Wei¹,

Li²,

Luo³

et al. 2020

Preprint

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Diabetes is caused by an interplay between genetics and environmental factors, tightly linked to lifestyle and dietary patterns. In this study, we explored the effectiveness of intermittent protein restriction (IPR) in diabetes control. IPR drastically reduced hyperglycemia in diabetic mice and enhanced b cell function and b cell proliferation in pancreatic islets. IPR also elevated insulin signaling in peripheral tissues with increased circulating FGF21 level. The changes of methionine/leucine are associated with the intervention activity of IPR. Single-cell RNA sequencing revealed that IPR reversed diabetes-mediated b cell reduction and immune cell accumulation in the islets of diabetic mice. The sequencing analysis also identified a small group of highly proliferative b cells that was elevated by IPR. As IPR is not based on calorie restriction and is highly effective in diabetes control and b cell protection, it has great potential to be widely applied to diabetic human subjects in the future.

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Section: Discussioncontrasting

confidence: 93%

Intermittent protein restriction improves glucose homeostasis and restores damaged islet beta cells in diabetic mice

Wei¹,

Li²,

Luo³

et al. 2020

Preprint

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“…This study also established that human fetal pancreatic C-peptide + /KI67 + cells expressed higher frequencies of CD9 + compared to the C-peptide + /KI67cells, confirming the higher proliferative status of the CD9 + fraction in vivo. As mentioned previously, recent findings from the Melton lab identified YAP as one factor that could drive proliferation of b-like cells while reducing their maturation when up-regulated during their differentiation (32,48). This group had also identified that WNT signaling was found in replicating epithelial progenitor cells and is down-regulated in mature endocrine-like cells (53).…”

Section: Caveats Linked To Promoting Proliferation During Hpsc Differmentioning

confidence: 79%

“…Screening primary human b-cells for mitogens that had been previously identified to initiate proliferation in rodent b-cells revealed that many factors were unable to initiate significant replication, with the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A)-inhibiting compound harmine being the only mitogen that induced significantly increased replication with treatment (31). Indeed, harmine is unique in that it has been repeatedly reported in the literature to induce bcell and other pancreatic cell replication (32)(33)(34)(35)(36)(37). Differing effects on b-cell replication through shared signaling mechanisms between rodent and human b-cells may be due to additional cellular factors that inhibit proliferation, such as the high accumulation of p16 in adult human b-cells (38)(39)(40).…”

Section: Comparison Of B-cell Proliferation Between Rodents and Humansmentioning

confidence: 99%

“…A notable report from the Melton group demonstrated that the leukemia inhibitory factor (LIF) drove proliferation in b-like cells expressing the corresponding receptor (LIFR). Activation of this pathway induced the expansion of b-like cells in vitro and was also able to enhance harmine-induced proliferation in treated b-like cells(32).…”

mentioning

confidence: 90%

“…At the stage where monohormonal hPSC-derived b-like cells emerge, only a small subset of end-stage b-like cells are actively replicating (~1%), as demonstrated using common markers of proliferation such as KI67 or 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays(5,32,48,50,51). As mentioned in the preceding section, modifications to the proliferation of pancreatic or endocrine progenitors can impact the final population of b-like cells, which demonstrates a balance that must be maintained between successful b-like cell production and progenitor cell expansion.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Harnessing Proliferation for the Expansion of Stem Cell-Derived Pancreatic Cells: Advantages and Limitations

Oakie

Nostro

2021

Front. Endocrinol.

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Restoring the number of glucose-responsive β-cells in patients living with diabetes is critical for achieving normoglycemia since functional β-cells are lost during the progression of both type 1 and 2 diabetes. Stem cell-derived β-cell replacement therapies offer an unprecedented opportunity to replace the lost β-cell mass, yet differentiation efficiencies and the final yield of insulin-expressing β-like cells are low when using established protocols. Driving cellular proliferation at targeted points during stem cell-derived pancreatic progenitor to β-like cell differentiation can serve as unique means to expand the final cell therapeutic product needed to restore insulin levels. Numerous studies have examined the effects of β-cell replication upon functionality, using primary islets in vitro and mouse models in vivo, yet studies that focus on proliferation in stem cell-derived pancreatic models are only just emerging in the field. This mini review will discuss the current literature on cell proliferation in pancreatic cells, with a focus on the proliferative state of stem cell-derived pancreatic progenitors and β-like cells during their differentiation and maturation. The benefits of inducing proliferation to increase the final number of β-like cells will be compared against limitations associated with driving replication, such as the blunted capacity of proliferating β-like cells to maintain optimal β-cell function. Potential strategies that may bypass the challenges induced by the up-regulation of cell cycle-associated factors during β-cell differentiation will be proposed.

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Islet organoid as a promising model for diabetes

Zhang

Song

et al. 2021

Protein Cell

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Studies on diabetes have long been hampered by a lack of authentic disease models that, ideally, should be unlimited and able to recapitulate the abnormalities involved in the development, structure, and function of human pancreatic islets under pathological conditions. Stem cell-based islet organoids faithfully recapitulate islet development in vitro and provide large amounts of three-dimensional functional islet biomimetic materials with a morphological structure and cellular composition similar to those of native islets. Thus, islet organoids hold great promise for modeling islet development and function, deciphering the mechanisms underlying the onset of diabetes, providing an in vitro human organ model for infection of viruses such as SARS-CoV-2, and contributing to drug screening and autologous islet transplantation. However, the currently established islet organoids are generally immature compared with native islets, and further efforts should be made to improve the heterogeneity and functionality of islet organoids, making it an authentic and informative disease model for diabetes. Here, we review the advances and challenges in the generation of islet organoids, focusing on human pluripotent stem cell-derived islet organoids, and the potential applications of islet organoids as disease models and regenerative therapies for diabetes.

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Identification of a LIF-Responsive, Replication-Competent Subpopulation of Human β Cells

Cited by 26 publications

References 58 publications

Intermittent protein restriction improves glucose homeostasis and restores damaged islet beta cells in diabetic mice

Intermittent protein restriction improves glucose homeostasis and restores damaged islet beta cells in diabetic mice

Harnessing Proliferation for the Expansion of Stem Cell-Derived Pancreatic Cells: Advantages and Limitations

Islet organoid as a promising model for diabetes

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