2020 Vol. 11, No. 2

Primate embryonic stem cells (ESCs), which have similar pluripotency to human ESCs, are a good model for studying interspecies chimerism and organ generation. In this study, Zhou et al. report an optimized culture medium that enhanced the anti-apoptotic ability of cmESCs and improved the development of chimeric embryos, in which domesticated cmESCs (D-ESCs) injected into pig blastocysts differentiated into cells of all three germ layers. Authors obtained two neonatal interspecies chimeras, in which they observed tissue-specific D-ESC differentiation. Taken together, the results demonstrate the capability of D-ESCs to integrate and differentiate into functional cells in a porcine model, with a chimeric ratio of 0.001–0.0001 in different neonate tissues. This work will facilitate future developments in xenogeneic organogenesis

Recollection
A 110-year-old wise man: Professor Libin T. Cheng, one of the founders of biochemistry and nutrition in China
He Zhang
2020, 11(2): 79-81. doi: 10.1007/s13238-017-0428-0
Abstract:
Commentary
Targeting oncogenic SOX2 in human cancer cells: therapeutic application
Shizhen Zhang, Yi Sun
2020, 11(2): 82-84. doi: 10.1007/s13238-019-00673-x
Abstract:
Review
Tissue-resident memory-like ILCs: innate counterparts of TRM cells
Xianwei Wang, Zhigang Tian, Hui Peng
2020, 11(2): 85-96. doi: 10.1007/s13238-019-0647-7
Abstract:
Innate lymphoid cells (ILCs) are defined as lymphocytes that lack RAG recombinase and do not express diverse antigen receptors; however, recent studies have revealed the adaptive features of ILCs. Mouse cytomegalovirus (MCMV)- and cytokine-induced memory natural killer (NK) cells circulate in the blood and are referred to as conventional memory NK cells. In contrast, virusand hapten-induced memory NK cells, hapten-induced memory ILC1s, and cytokine-induced memory-like ILC2s exhibit long-term residency in the liver or lung, and are referred to as tissue-resident memory ILCs. Considering their similar migration patterns and memory potential, tissue-resident memory ILCs could be regarded as innate counterparts of resident memory T (TRM) cells. Both tissue-resident memory ILCs and TRM cells share common characteristics in terms of dynamics, phenotype, and molecular regulation. The emergence of ILC memory expands the basic biology of ILCs and prompts us to re-examine their functions in disease progression. This review discusses the evidence supporting tissue-resident memory NK cells and other memory ILC subsets, compares them with TRM cells, and highlights key unsolved questions in this emerging field.
Research articles
Domesticated cynomolgus monkey embryonic stem cells allow the generation of neonatal interspecies chimeric pigs
Rui Fu, Dawei Yu, Jilong Ren, Chongyang Li, Jing Wang, Guihai Feng, Xuepeng Wang, Haifeng Wan, Tianda Li, Libin Wang, Ying Zhang, Tang Hai, Wei Li, Qi Zhou
2020, 11(2): 97-107. doi: 10.1007/s13238-019-00676-8
Abstract:
Blastocyst complementation by pluripotent stem cell (PSC) injection is believed to be the most promising method to generate xenogeneic organs. However, ethical issues prevent the study of human chimeras in the late embryonic stage of development. Primate embryonic stem cells (ESCs), which have similar pluripotency to human ESCs, are a good model for studying interspecies chimerism and organ generation. However, whether primate ESCs can be used in xenogenous grafts remains unclear. In this study, we evaluated the chimeric ability of cynomolgus monkey (Macaca fascicularis) ESCs (cmESCs) in pigs, which are excellent hosts because of their many similarities to humans. We report an optimized culture medium that enhanced the anti-apoptotic ability of cmESCs and improved the development of chimeric embryos, in which domesticated cmESCs (D-ESCs) injected into pig blastocysts differentiated into cells of all three germ layers. In addition, we obtained two neonatal interspecies chimeras, in which we observed tissue-specific D-ESC differentiation. Taken together, the results demonstrate the capability of D-ESCs to integrate and differentiate into functional cells in a porcine model, with a chimeric ratio of 0.001-0.0001 in different neonate tissues. We believe this work will facilitate future developments in xenogeneic organogenesis, bringing us one step closer to producing tissue-specific functional cells and organs in a large animal model through interspecies blastocyst complementation.
Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival
Dan Tong, Li Zhang, Fei Ning, Ying Xu, Xiaoyu Hu, Yan Shi
2020, 11(2): 108-123. doi: 10.1007/s13238-019-00662-0
Abstract:
Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vivo.
Structural insights into substrate recognition by the type VII secretion system
Shuhui Wang, Kaixuan Zhou, Xiaolin Yang, Bing Zhang, Yao Zhao, Yu Xiao, Xiuna Yang, Haitao Yang, Luke W. Guddat, Jun Li, Zihe Rao
2020, 11(2): 124-137. doi: 10.1007/s13238-019-00671-z
Abstract:
Type VII secretion systems (T7SSs) are found in many disease related bacteria including Mycobacterium tuberculosis (Mtb). ESX-1[early secreted antigen 6 kilodaltons (ESAT-6) system 1] is one of the five subtypes (ESX-1∼5) of T7SSs in Mtb, where it delivers virulence factors into host macrophages during infection. However, little is known about the molecular details as to how this occurs. Here, we provide high-resolution crystal structures of the C-terminal ATPase3 domains of EccC subunits from four different Mtb T7SS subtypes. These structures adopt a classic RecA-like α/β fold with a conserved Mg-ATP binding site. The structure of EccCb1 in complex with the C-terminal peptide of EsxB identifies the location of substrate recognition site and shows how the specific signaling module "LxxxMxF" for Mtb ESX-1 binds to this site resulting in a translation of the bulge loop. A comparison of all the ATPase3 structures shows there are significant differences in the shape and composition of the signal recognition pockets across the family, suggesting that distinct signaling sequences of substrates are required to be specifically recognized by different T7SSs. A hexameric model of the EccC-ATPase3 is proposed and shows the recognition pocket is located near the central substrate translocation channel. The diameter of the channel is ~25-Å, with a size that would allow helix-bundle shaped substrate proteins to bind and pass through. Thus, our work provides new molecular insights into substrate recognition for Mtb T7SS subtypes and also a possible transportation mechanism for substrate and/or virulence factor secretion.
Letters
USP47-mediated deubiquitination and stabilization of YAP contributes to the progression of colorectal cancer
Beiqing Pan, Yi Yang, Jian Li, Yu Wang, Chuantao Fang, Fa-Xing Yu, Yanhui Xu
2020, 11(2): 138-143. doi: 10.1007/s13238-019-00674-w
Abstract:
EGFR signaling augments TLR4 cell surface expression and function in macrophages via regulation of Rab5a activation
Jing Tang, Bowei Zhou, Melanie J. Scott, Linsong Chen, Dengming Lai, Erica K. Fan, Yuehua Li, Qiang Wu, Timothy R. Billiar, Mark A. Wilson, Ping Wang, Jie Fan
2020, 11(2): 144-149. doi: 10.1007/s13238-019-00668-8
Abstract:
DNMT3A reads and connects histone H3K36me2 to DNA methylation
Wenqi Xu, Jiahui Li, Bowen Rong, Bin Zhao, Mei Wang, Ruofei Dai, Qilong Chen, Hang Liu, Zhongkai Gu, Shuxian Liu, Rui Guo, Hongjie Shen, Feizhen Wu, Fei Lan
2020, 11(2): 150-154. doi: 10.1007/s13238-019-00672-y
Abstract: