Indolactam V/GLP-1-mediated differentiation of human iPS cells into glucose-responsive insulin-secreting progeny

Thatava, Tayaramma; Nelson, Timothy J.; Edukulla, Ramakrishna; Sakuma, Toshie; Ohmine, Seiga; Tonne, Jason M.; Yamada, Satsuki; Kudva, Yogish C.; Terzic, André; Ikeda, Yasuhiro

doi:10.1038/gt.2010.145

Cited by 99 publications

(99 citation statements)

References 49 publications

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“…It is thought that this response serves to protect the remaining betacells (reviewed in [109]). Indeed, the addition of GLP-1 to stem cell cultures has been reported to improve beta-cell development from human iPS cell-derived PDX1-positive precursors in vitro to the extent that some glucose responsiveness is generated [110].…”

Section: Generation Of Hormone-positive Cellsmentioning

confidence: 99%

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

Meulen¹,

Huising²

2014

Rev Diabet Stud

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■ AbstractType 1 diabetes (T1D) is a devastating disease precipitated by an autoimmune response directed at the insulinproducing beta-cells of the pancreas for which no cure exists. Stem cell-derived beta-cells show great promise for a cure as they have the potential to supply unlimited numbers of cells that could be derived from a patient's own cells, thus eliminating the need for immunosuppression. Current in vitro protocols for the differentiation of stem cell-derived beta-cells can successfully generate pancreatic endoderm cells. In diabetic rodents, such cells can differentiate further along the beta-cell lineage until they are eventually capable of restoring normoglycemia. While these observations demonstrate that stem cell-derived pancreatic endoderm has the potential to differentiate into mature, glucose-responsive beta-cells, the signals that direct differentiation and maturation from pancreatic endoderm onwards remain poorly understood. In this review, we analyze the sequence of events that culminates in the formation of beta-cells during embryonic development, and we summarize how current protocols to generate beta-cells have sought to capitalize on this ontogenic template. We place particular emphasis on the current challenges and opportunities which occur in the later stages of beta-cell differentiation and maturation of transplantable stem cell-derived beta-cells. Another focus is on the question how the use of recently identified maturation markers such as urocortin 3 can be instrumental in guiding these efforts.

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Section: Generation Of Hormone-positive Cellsmentioning

confidence: 99%

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

Meulen¹,

Huising²

2014

Rev Diabet Stud

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“…Diabetes-Reprogramming pluripotent cells to pancreatic ␤-like cells from a variety of animal species and humans is a critical step in creating an alternative source of insulin-producing cells (41)(42)(43). Different stepwise protocols that mimic the process of pancreatic development have been used for reprogramming, but the efficiency of the process is still very low, even using pancreatic ␤-cells as iPSC precursors (44).…”

Section: Testing Ipscs In Animal Disease Modelsmentioning

confidence: 99%

Preclinical Studies for Induced Pluripotent Stem Cell-based Therapeutics

Harding

Mirochnitchenko

2014

Journal of Biological Chemistry

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Induced pluripotent stem cells (iPSCs) and their differentiated derivatives can potentially be applied to cell-based therapy for human diseases. The properties of iPSCs are being studied intensively both to understand the basic biology of pluripotency and cellular differentiation and to solve problems associated with therapeutic applications. Examples of specific preclinical applications summarized briefly in this minireview include the use of iPSCs to treat diseases of the liver, nervous system, eye, and heart and metabolic conditions such as diabetes. Early stage studies illustrate the potential of iPSC-derived cells and have identified several challenges that must be addressed before moving to clinical trials. These include rigorous quality control and efficient production of required cell populations, improvement of cell survival and engraftment, and development of technologies to monitor transplanted cell behavior for extended periods of time. Problems related to immune rejection, genetic instability, and tumorigenicity must be solved. Testing the efficacy of iPSC-based therapies requires further improvement of animal models precisely recapitulating human disease conditions. The breakthrough discovery that specific sets of transcription factors can reprogram cell fate and generate induced pluripotent stem cells (iPSCs) 2 from various cell types has opened many new possibilities for research on cell states, differentiation, pluripotency, and general cell identity but, most importantly, has catalyzed the development of a whole new field of regenerative medicine (1). The field is still in a relatively early stage regarding a clear understanding of underlying developmental processes, cell behavior, and biological effects after cellgrafting experiments. The use of iPSCs and their products for human applications poses many new challenges from the experimental and regulatory points of view due to the unique properties of the cells and novel mechanism of their action.

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“…Two other signaling pathways, NOTCH and HEDGEHOG, have been shown to be involved in the DE differentiation into pancreatic endocrine cells [16] (Figure 1). The inhibition of HEDGEHOG-signaling by Cyclopamine or KAAD cyclopamine induces the generation of PDX1-expressing cells [17,18,25,27,29] , whereas Fibroblast growth factor 10 activates NOTCH signaling, which is involved in the proliferation of PDX1-expressing pancreatic progenitors.…”

Section: Differentiation Into Pancreatic Progenitors and Endocrine Cellsmentioning

confidence: 99%

“…In contrast to PDX1, NGN3 expression is stimulated by a reduction in NOTCH signaling. It has been previously shown that the blockage of NOTCH signaling at this stage may be driven by DAPT (the gamma secretase inhibitor) treatment and thus drive NGN3-expressing cells formation [17,18,27] . Interestingly, these cells have been found to be differentiated from PDX1-expressing pancreatic progenitors after specific treatments.…”

Section: Differentiation Into Pancreatic Progenitors and Endocrine Cellsmentioning

confidence: 99%

“…Therefore, a number of modifications in culture conditions have been done to improve the efficiency of β cell differentiation [16,18,25,26] . These modifications include, but are not limited to, monolayer cultures [16][17][18]25,27,28] or embryoid body (EB) technique [29,30] . Also, several studies have used xeno-free culture system to generate pancreatic β cells from PSCs in vitro [31][32][33][34] .…”

Section: Differentiation Of Pluripotent Stem Cells Into Insulin-secrementioning

confidence: 99%

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Advances and challenges in the differentiation of pluripotent stem cells into pancreatic β cells

Abdelalim

Emara

2015

WJSC

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Pluripotent stem cells (PSCs) are able to differentiate into several cell types, including pancreatic β cells. Differentiation of pancreatic β cells depends on certain transcription factors, which function in a coordinated way during pancreas development. The existing protocols for in vitro differentiation produce pancreatic β cells, which are not highly responsive to glucose stimulation except after their transplantation into immune-compromised mice and allowing several weeks for further differentiation to ensure the maturation of these cells in vivo . Thus, although the substantial improvement that has been made for the differentiation of induced PSCs and embryonic stem cells toward pancreatic β cells, several challenges still hindering their full generation. Here, we summarize recent advances in the differentiation of PSCs into pancreatic β cells and discuss the challenges facing their differentiation as well as the different applications of these potential PSC-derived β cells.

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Indolactam V/GLP-1-mediated differentiation of human iPS cells into glucose-responsive insulin-secreting progeny

Cited by 99 publications

References 49 publications

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

Preclinical Studies for Induced Pluripotent Stem Cell-based Therapeutics

Advances and challenges in the differentiation of pluripotent stem cells into pancreatic β cells

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