Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells

Yasunaga, Masahiro; Tada, Seiichiro; Torikai-Nishikawa, Satomi; Nakano, Yoko; Okada, Mitsuhiro; Jakt, Lars Martin; Nishikawa, Satomi; Chiba, Tsutomu; Era, Takumi; Nishikawa, Shin Ichi

doi:10.1038/nbt1167

Cited by 434 publications

(463 citation statements)

References 48 publications

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“…Activin A has been reported to induce definitive endoderm differentiation of ESCs;10, 32 DE cells constitute the embryonic germ layer that produces hepatic cells;33 aFGF and HGF are essential for liver development, with aFGF efficiently initiating hepatic differentiation of ESCs from the definitive endoderm and HGF promoting hepatic growth 34, 35. The novel growth factors delivery system was prepared by mixing Activin A, aFGF, and HGF with positively charged PEI‐MSNs.…”

Section: Resultsmentioning

confidence: 99%

Sustained Delivery Growth Factors with Polyethyleneimine‐Modified Nanoparticles Promote Embryonic Stem Cells Differentiation and Liver Regeneration

et al. 2016

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Stem‐cell‐derived hepatocyte transplantation is considered as a potential method for the therapy of acute and chronic liver failure. However, the low efficiency of differentiation into mature and functional hepatocytes remains a major challenge for clinical applications. By using polyethyleneimine‐modified silica nanoparticles, this study develops a system for sustained delivery of growth factors, leading to induce hepatocyte‐like cells (iHeps) from mouse embryonic stem cells (mESCs) and improve the expression of endoderm and hepatocyte‐specific genes and proteins significantly, thus producing a higher population of functional hepatocytes in vitro. When transplanted into liver‐injured mice after four weeks, mESC‐derived definitive endoderm cells treated with this delivery system show higher integration efficiency into the host liver, differentiated into iHeps in vivo and significantly restored the injured liver. Therefore, these findings reveal the multiple advantages of functionalized nanoparticles to serve as efficient delivery platforms to promote stem cell differentiation in the regenerative medicine.

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Section: Resultsmentioning

confidence: 99%

Sustained Delivery Growth Factors with Polyethyleneimine‐Modified Nanoparticles Promote Embryonic Stem Cells Differentiation and Liver Regeneration

et al. 2016

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“…4C). In addition, activin A can induce direct differentiation of hESCs toward definitive endoderm lineage (37)(38)(39). We compared activin A-treated H1-p53si cells with H1-null cells.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Apoptosis and Differentiation by p53 in Human Embryonic Stem Cells

Han

Qing

et al. 2007

Journal of Biological Chemistry

229

232

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The essentially infinite expansion potential and pluripotency of human embryonic stem cells (hESCs) makes them attractive for cell-based therapeutics. In contrast to mouse embryonic stem cells (mESCs), hESCs normally undergo high rates of spontaneous apoptosis and differentiation, making them difficult to maintain in culture. Here we demonstrate that p53 protein accumulates in apoptotic hESCs induced by agents that damage DNA. However, despite the accumulation of p53, it nevertheless fails to activate the transcription of its target genes. This inability of p53 to activate its target genes has not been observed in other cell types, including mESCs. We further demonstrate that p53 induces apoptosis of hESCs through a mitochondrial pathway. Reducing p53 expression in hESCs in turn reduces both DNA damage-induced apoptosis as well as spontaneous apoptosis. Reducing p53 expression also reduces spontaneous differentiation and slows the differentiation rate of hESCs. Our studies reveal the important roles of p53 as a critical mediator of human embryonic stem cells survival and differentiation.Human embryonic stem cells (hESCs) 3 are capable of essentially unlimited self-renewal and retain the developmental potential to differentiate into almost any cell type. These characteristics of hESCs make them attractive for tissue and cellbased therapies (1, 2). Previously, basic fibroblast growth factor and activin A were identified as self-renewal factors (3-6). However, for reasons that are not clear, hESCs often display high rates of spontaneous apoptosis and differentiation in culture, thus making the process of expanding these cells highly inefficient (3, 7-10). For example, Dravid et al. (8) reported that, under routine culture conditions, Ͼ30% of hESCs undergo spontaneous apoptosis. Furthermore, Ezashi et al. (12) showed that nearly 40% of hESCs undergo spontaneous differentiation after 12 days of culture in normoxic conditions. Finally, Maitra et al. (13) reported that multiple passages of hESCs can cause genomic alterations, which may limit the therapeutic application of hESCs. In contrast to hESCs, mouse embryonic stem cells (mESCs) undergo lower rates of spontaneous apoptosis and differentiation (14). Moreover, they maintain their pluripotency and genomic stability longer than hESCs (15). The reason for these different species-specific phenotypes in embryonic stem cells is currently unknown.The p53 tumor suppressor gene is a strong candidate for playing a role in the observed phenotypes of hESCs, because it regulates various cellular processes, including apoptosis, differentiation, and genomic integrity (16). In many cell types p53 plays a crucial role in controlling apoptosis and cell cycle arrest when these cells are exposed to stress-inducing conditions (17). In response to stress, p53 accumulates and transactivates downstream target genes such as mdm2 (responsible for the feedback degradation circuitry of p53), p21 (responsible for cell cycle control), bax, noxa, and puma (responsible for DNA damage-induced ...

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“…This might be due to the loss of some mesendodermal progenitors, such as Gsc þ cells, because these cells could further differentiate into definitive endodermal derivatives. 45 Another probability is that IP 3 R3 may have a direct effect on the later differentiation of endodermal derivatives. These possibilities need to be analyzed further.…”

Section: Discussionmentioning

confidence: 99%

Type 3 inositol 1,4,5-trisphosphate receptor negatively regulates apoptosis during mouse embryonic stem cell differentiation

Tang

et al. 2010

Cell Death Differ

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Ca 2 þ signals generated by inositol 1,4,5-trisphosphate receptors (IP 3 Rs) are crucial for cellular processes such as apoptosis and differentiation. However, the exact roles of IP 3 Rs and their contributions to Ca 2 þ signals in pluripotent embryonic stem (ES) cell behaviors remain largely unknown. In this study, we showed that the expression of type 3 IP 3 R (IP 3 R3) was transiently downregulated with a concomitant increase in apoptosis at the early differentiation stage of murine ES cells. Knockdown of IP 3 R3 by small interfering RNA increased apoptosis in differentiating cells but not in undifferentiated ES cells. Moreover, IP 3 R3 overexpression had the opposite effect. Consistently, IP 3 R3 knockdown altered Ca 2 þ oscillations in differentiating cells but not in undifferentiated ES cells. The apoptosis in differentiating IP 3 R3-knockdown cells was decreased by chelating intracellular Ca 2 þ with BAPTA-AM and increased in control ones. Furthermore, IP 3 R3 knockdown led to a suppression of the expression of mesodermal and mesoendodermal but not ectodermal markers. The differentiation suppressions were further confirmed by the impaired differentiation of mesodermal and some of the endodermal but not ectodermal derivatives. Such defects were partially because of the increased apoptosis in Flk-1 þ cells. These findings provide the first demonstration of the important role of IP 3 R3 in the regulation of apoptosis in early differentiating ES cells and subsequent lineage commitments through modulation of Ca 2 þ signals.

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Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells

Cited by 434 publications

References 48 publications

Sustained Delivery Growth Factors with Polyethyleneimine‐Modified Nanoparticles Promote Embryonic Stem Cells Differentiation and Liver Regeneration

Sustained Delivery Growth Factors with Polyethyleneimine‐Modified Nanoparticles Promote Embryonic Stem Cells Differentiation and Liver Regeneration

Regulation of Apoptosis and Differentiation by p53 in Human Embryonic Stem Cells

Type 3 inositol 1,4,5-trisphosphate receptor negatively regulates apoptosis during mouse embryonic stem cell differentiation

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