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源自人类多能干细胞的造血干细胞和祖细胞。

Haematopoietic stem and progenitor cells from human pluripotent stem cells.

作者信息

Sugimura Ryohichi, Jha Deepak Kumar, Han Areum, Soria-Valles Clara, da Rocha Edroaldo Lummertz, Lu Yi-Fen, Goettel Jeremy A, Serrao Erik, Rowe R Grant, Malleshaiah Mohan, Wong Irene, Sousa Patricia, Zhu Ted N, Ditadi Andrea, Keller Gordon, Engelman Alan N, Snapper Scott B, Doulatov Sergei, Daley George Q

机构信息

Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.

出版信息

Nature. 2017 May 25;545(7655):432-438. doi: 10.1038/nature22370. Epub 2017 May 17.

DOI:10.1038/nature22370
PMID:28514439
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5872146/
Abstract

A variety of tissue lineages can be differentiated from pluripotent stem cells by mimicking embryonic development through stepwise exposure to morphogens, or by conversion of one differentiated cell type into another by enforced expression of master transcription factors. Here, to yield functional human haematopoietic stem cells, we perform morphogen-directed differentiation of human pluripotent stem cells into haemogenic endothelium followed by screening of 26 candidate haematopoietic stem-cell-specifying transcription factors for their capacity to promote multi-lineage haematopoietic engraftment in mouse hosts. We recover seven transcription factors (ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1 and SPI1) that are sufficient to convert haemogenic endothelium into haematopoietic stem and progenitor cells that engraft myeloid, B and T cells in primary and secondary mouse recipients. Our combined approach of morphogen-driven differentiation and transcription-factor-mediated cell fate conversion produces haematopoietic stem and progenitor cells from pluripotent stem cells and holds promise for modelling haematopoietic disease in humanized mice and for therapeutic strategies in genetic blood disorders.

摘要

通过逐步暴露于形态发生素来模拟胚胎发育，或者通过强制表达主要转录因子将一种分化的细胞类型转化为另一种细胞类型，可以使多能干细胞分化出多种组织谱系。在这里，为了产生功能性人类造血干细胞，我们将人类多能干细胞进行形态发生素导向分化，使其成为造血内皮细胞，然后筛选26种候选造血干细胞特异性转录因子，以评估它们促进小鼠宿主多谱系造血植入的能力。我们获得了7种转录因子（ERG、HOXA5、HOXA9、HOXA10、LCOR、RUNX1和SPI1），这些转录因子足以将造血内皮细胞转化为造血干细胞和祖细胞，这些细胞能够在初代和二代小鼠受体中植入髓系、B细胞和T细胞。我们将形态发生素驱动的分化和转录因子介导的细胞命运转化相结合的方法，从多能干细胞中产生了造血干细胞和祖细胞，有望在人源化小鼠中模拟造血疾病，并为遗传性血液疾病提供治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecef/5872146/9ccb1c068b5e/nihms898882f13.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecef/5872146/b0da639339cc/nihms898882f7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecef/5872146/a759310546bd/nihms898882f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecef/5872146/6d6678e9fb62/nihms898882f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecef/5872146/a834e05b196a/nihms898882f11.jpg
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