Reprogramming mouse fibroblasts into engraftable myeloerythroid and lymphoid progenitors

Cheng, Hui; Ang, Heather; Farran, Chadi A. El; Пин, Ли; Fang, Hai Tong; Liu, Tongming; Kong, Say Li; Chin, Michael Lingzi; Ling, Wei; Lim, Erle C.H.; Li, Hu; Huber, Tara L.; Loh, Kyle M.; Loh, Yuin Han; Lim, Bing

doi:10.1038/ncomms13396

Cited by 26 publications

(25 citation statements)

References 71 publications

(101 reference statements)

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“…Ultimately, the safest HSCs generated in the dish would likely be genetically unaltered cells, produced by exposure to external factors equivalent to the embryonic cues that drive HSC development. Here, the bottleneck seems to be identifying the combinations of soluble and cell-based factors and (Vereide et al, 2014); (2) (Kyba et al, 2002;Lu et al, 2016); (3) ; (4) (Elcheva et al, 2014); note that GATA2/ SCL combination induces erythro-megakaryocytic differentiation (not shown); (5) (Sandler et al, 2014); (6) (Riddell et al, 2014); (7) ; (8) (Batta et al, 2014); (9) (Cheng et al, 2016); (10) (Pulecio et al, 2014); (11) (Lis et al, 2017); (12) (Sugimura et al, 2017). CLPs, common lymphoid progenitors; CMPs, common myeloid progenitors; MPPs, multipotent progenitors.…”

Section: Future Directions and Challengesmentioning

confidence: 99%

Human haematopoietic stem cell development: from the embryo to the dish

et al. 2017

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Haematopoietic stem cells (HSCs) emerge during embryogenesis and give rise to the adult haematopoietic system. Understanding how early haematopoietic development occurs is of fundamental importance for basic biology and medical sciences, but our knowledge is still limited compared with what we know of adult HSCs and their microenvironment. This is particularly true for human haematopoiesis, and is reflected in our current inability to recapitulate the development of HSCs from pluripotent stem cells in vitro. In this Review, we discuss what is known of human haematopoietic development: the anatomical sites at which it occurs, the different temporal waves of haematopoiesis, the emergence of the first HSCs and the signalling landscape of the haematopoietic niche. We also discuss the extent to which in vitro differentiation of human pluripotent stem cells recapitulates bona fide human developmental haematopoiesis, and outline some future directions in the field.

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Section: Future Directions and Challengesmentioning

confidence: 99%

Human haematopoietic stem cell development: from the embryo to the dish

et al. 2017

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“…In the case of endothelial cells, these are more difficult to obtain compared to fibroblasts, and constitute a very heterogeneous cell population in terms of phenotype, function and structure, which are organdependent 23 . Other studies have succeeded in reprogramming mouse fibroblasts into engraftable hematopoietic progenitors 24,25 yet, so far, no other protocol describes the generation of HSPC-like cells from human fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Hemogenic Reprogramming of Human Fibroblasts by Enforced Expression of Transcription Factors

Silvério-Alves

Gomes

Kurochkin

et al. 2019

JoVE

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The cellular and molecular mechanisms underlying specification of human hematopoietic stem cells (HSCs) remain elusive. Strategies to recapitulate human HSC emergence in vitro are required to overcome limitations in studying this complex developmental process. Here, we describe a protocol to generate hematopoietic stem and progenitor-like cells from human dermal fibroblasts employing a direct cell reprogramming approach. These cells transit through a hemogenic intermediate cell-type, resembling the endothelial-to-hematopoietic transition (EHT) characteristic of HSC specification. Fibroblasts were reprogrammed to hemogenic cells via transduction with GATA2, GFI1B and FOS transcription factors. This combination of three factors induced morphological changes, expression of hemogenic and hematopoietic markers and dynamic EHT transcriptional programs. Reprogrammed cells generate hematopoietic progeny and repopulate immunodeficient mice for three months. This protocol can be adapted towards the mechanistic dissection of the human EHT process as exemplified here by defining GATA2 targets during the early phases of reprogramming. Thus, human hemogenic reprogramming provides a simple and tractable approach to identify novel markers and regulators of human HSC emergence. In the future, faithful induction of hemogenic fate in fibroblasts may lead to the generation of patient-specific HSCs for transplantation.

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“…More recently, a group used Scl, Lmo2, Runx1 and Bmi1 overexpression in MEFs to generate multipotent haematopoietic cells with some B lymphoid potential ( Fig. 1, pink labels) [18]. By means of small-molecule inhibition, this study also showed that signalling through Bmp4 and Mapk/Erk pathways is required for their reprogramming platform, shedding some light on the mechanism of fibroblastto-haematopoietic conversion.…”

Section: Direct Conversion Of Somatic Cells To Haematopoietic Stem Anmentioning

confidence: 71%

“…1, orange labels). 1, pink labels) [18]. MEFs and MAFs from p53 -/mice yielded more efficient reprogramming than the wild-type counterparts, but the engraftment potential of the resulting cells remained negligible.…”

Section: Direct Conversion Of Somatic Cells To Haematopoietic Stem Anmentioning

confidence: 99%

Haematopoietic stem cell reprogramming and the hope for a universal blood product

2019

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Edited by Catherine RobinHaematopoietic stem cells (HSCs) are the only adult stem cells with a demonstrated clinical use, even though a tractable method to maintain and expand human HSCs in vitro has not yet been found. Owing to the introduction of transplantation strategies for the treatment of haematological malignancies and, more recently, the promise of gene therapy, the need to improve the generation, manipulation and scalability of autologous or allogeneic HSCs has risen steeply over the past decade. In that context, reprogramming strategies based on the expression of exogenous transcription factors have emerged as a means to produce functional HSCs in vitro. These approaches largely stem from the assumption that key master transcription factors direct the expression of downstream target genes thereby triggering haematopoiesis. Both somatic and pluripotent cells have been used to this end, yielding variable results in terms of haematopoietic phenotype and functionality. Here, we present an overview of the haematopoietic reprogramming methods reported to date, provide the appropriate historical context and offer some critical insight about where the field stands at present.

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Reprogramming mouse fibroblasts into engraftable myeloerythroid and lymphoid progenitors

Cited by 26 publications

References 71 publications

Human haematopoietic stem cell development: from the embryo to the dish

Human haematopoietic stem cell development: from the embryo to the dish

Hemogenic Reprogramming of Human Fibroblasts by Enforced Expression of Transcription Factors

Haematopoietic stem cell reprogramming and the hope for a universal blood product

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