On September 13, the international academic journal Cell Research published online the latest research result "Integrin αEβ7+ T cells direct intestinal stem cell fate decisions via adhesion signaling" completed by Chen Jianfeng's research group and Zeng Yi's research group from HIAS, UCAS/CAS Centerfor Excellence in Molecular Cell Science (CEMCS) (Shanghai Institute of Biochemistry and Cell Biology) in cooperation with Zeng An's research group from CEMCS. The study finds that a new mechanism where integrin αEβ7 expressed on intestinal T cells binds to E-cadherin on intestinal stem cells (ISCs) and directs the proliferation and differentiation fate of intestinal epithelial cells (IECs) by altering the signaling downstream of E-cadherin adhesions, thus maintaining intestinal homeostasis.
Rapid renewal of intestinal epithelia is an important vital activity to maintain intestinal homeostasis. Intestinal epithelial renewal begins with the response of receptors on ISCs to signals from their surrounding microenvironment, which then determines the differentiation propensities of ISCs by regulating different differentiation signals. In this way, ISCs differentiate into terminal cells with different functions. Immune cells, as a new member of the ISC microenvironment, have attracted much attention. However, there is still little knowledge about whether and how immune cells are involved in regulating the plasticity of IECs in normal physiological states.
The study finds that T cells in the intestinal crypt adhere to ISCs, which is mediated by the adhesion molecule E-cadherin of integrin αEβ7 on the surface of T cells and ISCs. Intestinal T lymphocyte depletion results in skewed IEC proliferation and differentiation. Adoptive T cell transfer can restore the skewed IEC differentiation in integrin β7 knockout mice. Results of single-cell transcriptome sequencing and other experiments show that the Wnt signaling pathway is inhibited in ISCs and TA cells of integrin β7 knockout mice, while the Notch signaling pathway and cell cycle-related gene expression are up-regulated. Further molecular mechanism studies show that intestinal T cells bind to E-cadherin on epithelial cells through the surface integrin αEβ7, and regulate Wnt and Notch signaling pathways through E-cadherin internalization, thus regulating the differentiation of IECs. In summary, the study finds that intestinal lymphocytes can regulate the plasticity of IECs at a single cell level via contact with IECs, and proposes the concept that αEβ7−cadherin-mediated intercellular adhesion signals direct ISC fate decisions. These findings will broaden people's understanding of the regulation of cellular plasticity and highlight the importance of adhesion signaling provided by lymphocytes in determining the fate of ISCs.
Chen Shiyang, a postdoctoral fellow at HIAS, UCAS, and Zheng Yajuan and Dr. Ran Xiaojuan from CEMCS are the co-first authors. Research Fellow Chen Jianfeng and Research Fellow Zeng Yi from HIAS, UCAS/CEMCS and Research Fellow Zeng An from CEMCS are co-corresponding authors. The study was funded by the National Natural Science Foundation of China, the Ministry of Science and Technology of the People's Republic of China, and the CAS Strategic Priority Research Program. The study was carried out with strong support from the molecular biology technology platform, cell analysis technology platform and laboratory animal platform of CEMCS. Special thanks go to CEMCS Research Fellow Li Lin, Research Fellow Ge Gaoxiang, and Research Fellow Wang Hongyan, and Prof. Wu Dianqing at Yale School of Medicine.
Article link: https://www.nature.com/articles/s41422-021-00561-2
