Direct Reprogramming of Fibroblasts via a Chemically Induced XEN-like State

Li, Xiang; Liu, Defang; Ma, Yantao; Du, Xiaomin; Jing, Junzhan; Wang, Lipeng; Xie, Bingqing; Sun, Dihua; Sun, Shaoqiang; Jin, Xin; Zhang, Xu; Zhao, Ting; Guan, Jingyang; Yi, Zexuan; Lai, Weifeng; Zheng, Ping; Huang, Zhuo; Chang, Yan‐Zhong; Chai, Zhen; Xu, Jun; Deng, Hongkui

doi:10.1016/j.stem.2017.05.019

Cited by 78 publications

(59 citation statements)

References 33 publications

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“…[5][6][7][8][9] Murine and canine XEN cell lines maintained in vitro represent a PrE lineage. 11,12 Two master genes of pluripotency, Sall4 and Pigs are an ideal model for many human diseases and a potential source for organ transplantation. 11,12 Two master genes of pluripotency, Sall4 and Pigs are an ideal model for many human diseases and a potential source for organ transplantation.…”

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confidence: 99%

Characterization of porcine extraembryonic endoderm cells

Shen

Zhang

et al. 2019

Cell Proliferation

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Objectives To date, many efforts have been made to establish porcine embryonic stem (pES) cells without success. Extraembryonic endoderm (XEN) cells can self‐renew and differentiate into the visceral endoderm and parietal endoderm. XEN cells are derived from the primitive endoderm of the inner cell mass of blastocysts and may be an intermediate state in cell reprogramming. Materials and methods Porcine XEN cells (pXENCs) were generated from porcine pluripotent stem cells (pPSCs) and were characterized by RNA sequencing and immunofluorescence analyses. The developmental potential of pXENCs was investigated in chimeric mouse embryos. Results Porcine XEN cells derived from porcine pPSCs were successfully expanded in N2B27 medium supplemented with bFGF for least 30 passages. RNA sequencing and immunofluorescence analyses showed that pXENCs expressed the murine and canine XEN markers Gata6 , Gata4 , Sox17 and Pdgfra but not the pluripotent markers Oct4 , Sox2 and TE marker Cdx2 . Moreover, these cells contributed to the XEN when injected into four‐cell stage mouse embryos. Supplementation with Chir99021 and SB431542 promoted the pluripotency of the pXENCs. Conclusions We successfully derived pXENCs and showed that supplementation with Chir99021 and SB431542 confer them with pluripotency. Our results provide a new resource for investigating the reprogramming mechanism of porcine‐induced pluripotent stem cells.

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confidence: 99%

Characterization of porcine extraembryonic endoderm cells

Shen

Zhang

et al. 2019

Cell Proliferation

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“…Transplantation of parenchymal stem cells might aid in reinstating the regenerative ability (20–38), but efficient engraftment of parenchymal cells is handicapped by the prohibitive fibrotic microenvironment in diseased organs. Therefore, designing effective cell therapy strategies requires understanding how microenvironmental cues regulate parenchymal regeneration and fibrosis in the damaged lung and liver (39–47).…”

Section: Introductionmentioning

confidence: 99%

Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis

Cao

Sun

et al. 2017

Sci. Transl. Med.

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The regenerative capacity of lung and liver is sometimes impaired by chronic or overwhelming injury. Orthotopic transplantation of parenchymal stem cells to damaged organs might reinstate their self-repair ability. However, parenchymal cell engraftment is frequently hampered by the microenvironment in diseased recipient organs. Here, we show that targeting both the vascular niche and perivascular fibroblasts establishes “hospitable soil” to foster incorporation of “seed”, in this case the engraftment of parenchymal cells in injured organs. Specifically, ectopic induction of endothelial cell (EC)-expressed paracrine/angiocrine hepatocyte growth factor (HGF) and inhibition of perivascular NADPH Oxidase 4 (NOX4) synergistically enabled reconstitution of mouse and human parenchymal cells in damaged organs. Reciprocally, genetic knockout of Hgf in mouse ECs (HgfiΔEC/iΔEC) aberrantly upregulated perivascular NOX4 during liver and lung regeneration. Dysregulated HGF and NOX4 pathways subverted the function of vascular and perivascular cells from an epithelially-inductive niche to a microenvironment that inhibited parenchymal reconstitution. Perivascular NOX4 induction in HgfiΔEC/iΔEC mice recapitulated the phenotype of human and mouse fibrotic livers and lungs. Consequently, EC-directed HGF and NOX4 inhibitor GKT137831 stimulated regenerative integration of mouse and human parenchymal cells in chronically injured lung and liver. Our data suggest that targeting dysfunctional perivascular and vascular cells in diseased organs can bypass fibrosis and enable reparative cell engraftment to reinstate lung and liver regeneration.

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“…Before using iPSCs clinically, the inserted transgenes have to be either deleted or effectively silenced after the cells have been reprogrammed. With other approaches, for example using nonintegrating vectors [104,105] , introduction of stemness proteins [106,107] , or pharmaceutically with a suitable combination of small molecules, have been developed to address this problem to a certain extent [44,108,109] . Recently, a new method to generate iPSCs with CRISPR activation through precise epigenetic remodeling of endogenous loci shed light on how targeted chromatin remodeling triggers pluripotency induction [110] .…”

Section: Progress On Inducing Pluripotent Stem Cells Of Pig and Othermentioning

confidence: 99%

Porcine pluripotent stem cells: progress, challenges and prospects

Han¹,

Miao²,

Hua³

et al. 2019

Front. Agr. Sci. Eng.

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Pluripotent stem cells (PSCs) are characterized by their capacity for high self-renewal and multiple differentiation potential and include embryonic stem cells, embryonic germ cells and induced PSCs. PSCs provide a very suitable model for the studies of human diseases, drugs screening, regenerative medicine and developmental biology research. Pigs are considered as an ideal model for preclinical development of human xenotransplantation, therapeutic approaches and regenerative medicine because of their size and physiological similarity to humans. However, lack of knowledge about the derivation, characterization and pluripotency mechanisms of porcine PSCs hinders progress in these biotechnologies. In this review, we discuss the latest progress on porcine PSCs generation, evaluation criteria for pluripotency, the scientific and technical questions arising from these studies. We also introduce our perspectives on porcine PSC research, in the hope of providing new ideas for generating naive porcine PSCs and animal breeding.

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Direct Reprogramming of Fibroblasts via a Chemically Induced XEN-like State

Cited by 78 publications

References 33 publications

Characterization of porcine extraembryonic endoderm cells

Characterization of porcine extraembryonic endoderm cells

Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis

Porcine pluripotent stem cells: progress, challenges and prospects

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