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Myeloid, B, and T lineage regeneration from pluripotent stem cells by defined transcription factors

ABSTRACT: Myeloid, B, and T lineage regeneration from pluripotent stem cells by defined transcription factors

PROVIDER: PRJNA784299 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17055686_1.fastq.gz	Fastqsanger.gz
	SRR17055686_2.fastq.gz	Fastqsanger.gz
	SRR17055687_1.fastq.gz	Fastqsanger.gz
	SRR17055687_2.fastq.gz	Fastqsanger.gz
	SRR17055688_1.fastq.gz	Fastqsanger.gz

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Myeloid, B, and T lineage regeneration from pluripotent stem cells by defined transcription factors

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Myeloid, B, and T lineage regeneration from pluripotent stem cells by defined transcription factors

Project description:Generating prolonged multi-lineage hematopoiesis from pluripotent stem cells (PSCs), an unlimited cell source, is a crucial aim for regenerative hematology. In this study, we used a gene-edited PSC line and revealed that simultaneous expression of three transcription factors, Runx1, Hoxa9, and Hoxa10, drove robust emergence of induced hematopoietic progenitor cells (iHPCs). The iHPCs engrafted successfully in wild type animals and repopulated abundant and complete myeloid, B, and T lineage mature cells in primary and secondary C57BL/6 recipients. The regenerative multi-lineage hematopoiesis distributed normally in multiple organs, persisted over six months, and eventually declined over time with no leukemogenesis. Transcriptome characterization of regenerative myeloid, B, and T cells at the single cell resolution further projected their identities to natural cell counterparts. Thus, we provide strong genetic evidence that co-expression of exogenous Runx1, Hoxa9, and Hoxa10 simultaneously leads to long-term reconstitution of myeloid, B, and T lineages using PSC-derived iHPCs as cell source.

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T cell regeneration from pluripotent stem cells by defined transcription factors

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Project description:We identified that synergistic and inducible expression of specific transcription factors in pluripotent stem cells gave rise to engraftable iHPC capable of developing into multiple lineages including myeloid cells, T cells, and B cells in the C57BL/6 recipients. The regenerative myeloid, T, and B cells were detected in multiple tissues including peripheral blood, bone marrow and spleen. We performed single cell RNA-seq on the sorted GFP+CD45.2+ cells from the peripheral blood of recipients at 16 weeks after iHPC transplantation. Single-cell transcriptome illustrated the existence of regenerative myeloid cells, T cells, and B cells. The cell hierarchy of regenerative myeloid cells, T cells, and B cells in vivo resembles those of natural counterparts.

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Project description:Differentiation of mammalian pluripotent cells involves large-scale changes in transcription and, among the molecules that orchestrate these changes, chromatin remodellers are essential to initiate, establish and maintain a new gene regulatory network. The NuRD complex is a highly conserved chromatin remodeller which fine-tunes gene expression in embryonic stem cells. While the function of NuRD in mouse pluripotent cells has been well defined, no study yet has defined NuRD function in human pluripotent cells. We investigated the structure and function of NuRD in human induced pluripotent stem cells (hiPSCs). Using immunoprecipitation followed by mass-spectrometry in hiPSCs and in naive or primed mouse pluripotent stem cells, we find that NuRD structure and biochemical interactors are generally conserved. Using RNA sequencing, we find that, whereas in mouse primed stem cells and in mouse naive ES cells, NuRD is required for an appropriate level of transcriptional response to differentiation signals, hiPSCs require NuRD to initiate these responses. This difference indicates that mouse and human cells interpret and respond to induction of differentiation differently.

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