Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

Guo, Rong; Hu, Fang; Weng, Qitong; Lv, Chen; Wu, Hongling; Liu, Lijuan; Li, Zongcheng; Zeng, Yang; Bai, Zhijie; Zhang, Mengyun; Liu, Yuting; Liu, Xiaofei; Xia, Chengxiang; Wang, Tongjie; Zhou, Pingwei; Wang, Kaitao; Dong, Yong; Luo, Yuxuan; Zhang, Xiangzhong; Guan, Yuxian; Yang, Geng; Du, Juan; Li, Yangqiu; Lan, Yu; Chen, Jiekai; Liu, Bing; Wang, Jinyong

doi:10.1038/s41422-019-0251-7

Cited by 45 publications

(55 citation statements)

References 73 publications

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“…Runx1 , a member of the Runx (transcription factor associated with runt) family, has been shown to regulate the differentiation of hematopoietic stem cells into mature blood cells ( Cai et al, 2015 ; Guo et al, 2020 ). In addition, Runx1 may play an important role in the phenotype maintain and differentiation of osteoblasts and chondrocyte lineages ( LeBlanc et al, 2015 ; Tang J. et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Long Non-coding RNA 332443 Inhibits Preadipocyte Differentiation by Targeting Runx1 and p38-MAPK and ERK1/2-MAPK Signaling Pathways

Xiao

Tang

et al. 2021

Front. Cell Dev. Biol.

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Long non-coding RNAs (lncRNAs) have emerged as integral regulators of pathophysiological processes, but their specific roles and mechanisms in adipose tissue development remain largely unknown. Here, through microarray analysis, co-expression, and tissue specific analysis of adipocyte tissues after fasting for 72 h, we found that Lnc-FR332443 expression was dramatically decreased, as well as the expression of Runx1. The UCSC database and Ensembl database indicated that Lnc-FR332443 is the antisense lncRNA of Runx1. Lnc-FR332443 and Runx1 are highly enriched in adipose tissue and downregulated during adipogenic differentiation. Adipose tissue-specific knockdown of Lnc-FR332443 increased fat mass in vivo, and specific knockdown of Lnc-FR332443 in 3T3-L1 preadipocytes promoted adipogenic differentiation. In this process, Runx1 expression was decreased when Lnc-FR332443 was downregulated in adipocytes or 3T3-L1 preadipocytes, and vice versa, when Lnc-FR332443 was upregulated, the expression of Runx1 was increased. However, overexpression of Runx1 decreased the expression of the adipocyte cell marker genes PPARγ, C/EBPα and FABP4 significantly, while not affected the expression of Lnc-FR332443. Mechanistically, Lnc-FR332443 positively regulates Runx1 expression in mouse adipocytes and suppresses adipocyte differentiation by attenuating the phosphorylation of MAPK-p38 and MAPK-ERK1/2 expression. Thus, this study indicated that Lnc-FR332443 inhibits adipogenesis and which might be a drug target for the prevention and treatment of obesity.

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Section: Introductionmentioning

confidence: 99%

Long Non-coding RNA 332443 Inhibits Preadipocyte Differentiation by Targeting Runx1 and p38-MAPK and ERK1/2-MAPK Signaling Pathways

Xiao

Tang

et al. 2021

Front. Cell Dev. Biol.

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“…In this study, we identify that synergistic expression of Runx1, Hoxa9 , and Lhx2 dominantly confers B cell lineage fate on PSC-derived iHPCs and leads to complete B lymphopoiesis in vivo following a differentiation scheme we previously reported (Guo et al, 2020; Wang et al, 2020). The regenerative B (iB) cells, including B-1a, B-1b, FO B, and MZ B subsets, possess a diversity of BCR repertoires similar to their natural B cell counterparts.…”

Section: Introductionmentioning

confidence: 64%

“…pre-HSC isolated from YS and P-Sp also are capable of producing B-1 and B-2 cells (Hadland et al, 2017; Kobayashi et al, 2019), signaling that the B-1 and B-2 cell fate are determined preceding the emergence of definitive HSC. Our group have recently reported that induced hemogenic endothelial progenitors (iHECs), derived from embryonic stem cells with inducible expression of Runx1 and Hoxa9 , can generate induced hematopoietic progenitor cells (iHPCs) preferentially contributing to functional T cells in vivo (Guo et al, 2020). Thus, regeneration of lymphopoiesis from PSCs can be achieved in the absence of regenerative HSCs.…”

Section: Introductionmentioning

confidence: 99%

Regeneration of humoral immunity from pluripotent stem cells by defined transcription factors

Zhang

Weng

et al. 2021

Preprint

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Regeneration of humoral immunity from pluripotent stem cells (PSCs) is a crucial aim in translational medicine. However, reconstitution of complete, sustained, and functional B lymphopoiesis from PSCs has not yet been developed. Here, we successfully achieved regenerative B lymphopoiesis in B-cell deficient animals transplanted with PSC-derived hematopoietic progenitors (iHPCs) guided by synergistic expression of Runx1, Hoxa9, and Lhx2. Upon transplantation, the iHPCs immediately gave rise to pro/pre-B cells in recipients' bone marrow, which were able to further differentiate into the entire B cell lineages, including innate B-1a, B-1b, MZ B cells, as well as adaptive FO B cells. In responding to antigen stimuli, the regenerative B cells produced adaptive humoral immune responses, sustained a prolonged antigen-specific antibody production, and formed immune-memory. Particularly, the regenerative B cells in spleen showed developing patterns of immunoglobulin chain-switch and hyper-mutation via a cross-talk with the host T follicular helper cells, which eventually formed T cell-dependent humoral responses. This study provides de novo evidence that B lymphopoiesis can be regenerated from PSCs via a HSC-independent approach, which provides insights into treating B-cell related humoral deficiencies using PSCs as unlimited cell resource.

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“…In this protocol, hematopoietic progenitors with thymus-homing abilities were generated by the expression of RUNX1 and HOXA9 at the endothelial-to-hematopoietic transition stage. Upon engraftment, these induced progenitor cells gave rise to T-cells that restore immune surveillance in immune-deficient mice ( 166 ).…”

Section: Immune Cell Programming and Reprogrammingmentioning

confidence: 99%

Cell Fate Reprogramming in the Era of Cancer Immunotherapy

et al. 2021

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Advances in understanding how cancer cells interact with the immune system allowed the development of immunotherapeutic strategies, harnessing patients’ immune system to fight cancer. Dendritic cell-based vaccines are being explored to reactivate anti-tumor adaptive immunity. Immune checkpoint inhibitors and chimeric antigen receptor T-cells (CAR T) were however the main approaches that catapulted the therapeutic success of immunotherapy. Despite their success across a broad range of human cancers, many challenges remain for basic understanding and clinical progress as only a minority of patients benefit from immunotherapy. In addition, cellular immunotherapies face important limitations imposed by the availability and quality of immune cells isolated from donors. Cell fate reprogramming is offering interesting alternatives to meet these challenges. Induced pluripotent stem cell (iPSC) technology not only enables studying immune cell specification but also serves as a platform for the differentiation of a myriad of clinically useful immune cells including T-cells, NK cells, or monocytes at scale. Moreover, the utilization of iPSCs allows introduction of genetic modifications and generation of T/NK cells with enhanced anti-tumor properties. Immune cells, such as macrophages and dendritic cells, can also be generated by direct cellular reprogramming employing lineage-specific master regulators bypassing the pluripotent stage. Thus, the cellular reprogramming toolbox is now providing the means to address the potential of patient-tailored immune cell types for cancer immunotherapy. In parallel, development of viral vectors for gene delivery has opened the door for in vivo reprogramming in regenerative medicine, an elegant strategy circumventing the current limitations of in vitro cell manipulation. An analogous paradigm has been recently developed in cancer immunotherapy by the generation of CAR T-cells in vivo. These new ideas on endogenous reprogramming, cross-fertilized from the fields of regenerative medicine and gene therapy, are opening exciting avenues for direct modulation of immune or tumor cells in situ, widening our strategies to remove cancer immunotherapy roadblocks. Here, we review current strategies for cancer immunotherapy, summarize technologies for generation of immune cells by cell fate reprogramming as well as highlight the future potential of inducing these unique cell identities in vivo, providing new and exciting tools for the fast-paced field of cancer immunotherapy.

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Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

Cited by 45 publications

References 73 publications

Long Non-coding RNA 332443 Inhibits Preadipocyte Differentiation by Targeting Runx1 and p38-MAPK and ERK1/2-MAPK Signaling Pathways

Long Non-coding RNA 332443 Inhibits Preadipocyte Differentiation by Targeting Runx1 and p38-MAPK and ERK1/2-MAPK Signaling Pathways

Regeneration of humoral immunity from pluripotent stem cells by defined transcription factors

Cell Fate Reprogramming in the Era of Cancer Immunotherapy

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