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ERK5 kinase and application of ERK5 inhibitor in stem cell differentiation

A stem cell differentiation and stem cell technology, applied to embryonic cells, germ cells, animal cells, etc., can solve problems such as differentiation difficulties

Active Publication Date: 2020-05-01
UNIVERSITY OF MACAU
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, there are still many difficulties in regulating the differentiation of human pluripotent stem cells such as human embryonic stem cells (hESCs) into specific cell types

Method used

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  • ERK5 kinase and application of ERK5 inhibitor in stem cell differentiation
  • ERK5 kinase and application of ERK5 inhibitor in stem cell differentiation
  • ERK5 kinase and application of ERK5 inhibitor in stem cell differentiation

Examples

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Effect test

experiment example 1

[0070] ERK5 is essential for maintaining the pluripotency (Pluripotency) of hESCs

[0071] hESCs can maintain unlimited self-renewal and pluripotency, and the genes that maintain pluripotency are widely recognized, NANOG, SOX2 and OCT4. FGF2 and TGFβ are essential for pluripotency maintenance in hESCs for triggering ERK1 / 2 and SMAD2 / 3 phosphorylation to promote NANOG expression. ERK5 is a member of the MAPK family, and experimental results prove that it is also necessary for the maintenance of pluripotency of hESCs. Small molecule chemical inhibitors, ERK5-IN-1, BIX02189 and XMD892 were used in the experiments. ERK5-IN-1 inhibits the binding of ERK5 activators to cell surface receptors, BIX02189 inhibits the phosphorylation of ERK5 by MEK5, and XMD892 inhibits the transcription of ERK5 further phosphorylated into the nucleus. The three inhibitors were added to the E8 medium where hESCs were normally pluripotent, and the inhibitory effect was from day 1 to day 6. All three in...

experiment example 2

[0076] ERK5 Inhibitor Promotes Differentiation of Neuro Progenitor Cells

[0077] In mammalian development, early differentiation of the nervous system belongs to ectodermal development. It has been reported that TGFβ pathway and BMP pathway play a very important and decisive role in the induction of ectoderm. In our experimental system, under the condition of autonomous differentiation in which FGF2 and TGFβ growth factors were removed from E8 medium, after 4 days of differentiation, the ERK5 inhibitor XMD892 not only reduced the expression of pluripotency genes, but also promoted the induction of neural Gene expression level of PAX6 in neuro progenitor cells. Its gene expression level was similar in intensity to TGFβ inhibition (SB431542) or dual inhibition of BMP4 and TGFβ (LDN193189+SB431542) ( figure 2 A). The shape of the cells is shown in the figure ( figure 2 C). What is more noteworthy is that XMD892 not only promotes early neural development, but also greatly ...

experiment example 3

[0080] ERK5 Inhibitor Enhances Extra-embryonic Cells Differentiation and Suppresses Mesoderm Differentiation

[0081] In the in vitro culture of stem cells, hESCs can not only differentiate into the cell types of the three germ layers, endoderm (Endoderm), mesoderm (Mesoderm) and ectoderm (Ectoderm), but also reverse the cell fate and differentiate into the trophoblast of the extraembryonic layer. (Trophoblast) cells. In 2002, Xu et al. (Xu, R.H., et al., BMP4initiates humanembryonic stem cell differentiation to trophoblast.Nature Biotechnology, 2002.20(12):p.1261-1264) proposed that extraembryonic cell types can be differentiated in hESCs After the trophoblast, it greatly complements the application of hESCs in stem cell differentiation. BMP4 can promote trophoblast differentiation in the absence of FGF2, showing extremely high expression of CGA and CGB. The inhibition of TGFβ pathway (SB431542) can cooperate with the action of BMP4 to greatly promote the expression of CGA ...

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Abstract

The invention discloses an ERK5 kinase and application of an ERK5 inhibitor in stem cell differentiation, and relates to the technology of stem cell differentiation regulation. Research shows that ERK5 plays an important role in the differentiation of stem cells and the ERK5 inhibitor can regulate the differentiation direction of stem cells; therefore, the ERK5 inhibitor has the application in thepreparation of any of the following reagents: (1) a reagent for regulating the differentiation of stem cells toward nerve cells, and the nerve cells are neural progenitor cells or neural crest cells;(2) an agent for regulating the differentiation of stem cells toward a germ layer, the germ layer is a trophoblast or mesoderm; and (3) an agent for promoting the differentiation of stem cells into cardiomyocytes. A new idea is provided for the differentiation of the stem cells.

Description

technical field [0001] The invention relates to the technical field of stem cell differentiation regulation, in particular to the application of ERK5 kinase and its inhibitor in stem cell differentiation. Background technique [0002] Human pluripotent stem cells (hPSCs) can differentiate into all cell types in our body and are an important model system for studying human embryonic development. Specific cell types generated by hPSC differentiation are of great interest in cell therapy, drug screening, and disease model studies. [0003] However, there are still many difficulties in regulating the differentiation of human pluripotent stem cells such as human embryonic stem cells (hESCs) into specific cell types. [0004] In view of this, the present invention is proposed. Contents of the invention [0005] The purpose of the present invention is to provide the application of ERK5 inhibitor in regulation or regulation of stem cell differentiation. The research of the pres...

Claims

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Application Information

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IPC IPC(8): C12N5/0735C12N5/071C12N5/0797
CPCC12N5/0618C12N5/0657C12N5/0606C12N2501/727
Inventor 陈国凯宋程程
Owner UNIVERSITY OF MACAU
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