Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming

Gomes, Andreia; Kurochkin, Ilia; Chang, Betty; Daniel, Michael G.; Law, Kenneth; Satija, Namita; Lachmann, Alexander; Wang, Zichen; Ferreira, Lino; Ma’ayan, Avi; Chen, Benjamin; Papatsenko, Dmitri; Lemischka, Ihor R.; Moore, Kateri; Pereira, Carlos Filipe

doi:10.1016/j.celrep.2018.11.032

Cited by 30 publications

(51 citation statements)

References 62 publications

(91 reference statements)

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“…Enrichment tests were performed for custom gene sets extracted from prior literature and for gene sets associated with specific gene ontology (GO) terms [44,45]. RNAseq data from Gomes et al [30] was used for comparative purposes. Normalized read counts for all relevant samples were plotted using GRAPH-PAD PRISM 7 software.…”

Section: Rnaseq Analysismentioning

confidence: 99%

“…We recently demonstrated that three TFs, GATA2, GFI1B, and FOS, were sufficient to induce a hemogenic program in human fibroblasts [30]. Transplantation of CD49f + cells sorted at Day 25 of reprogramming in immunocompromised mice resulted in short-term multilineage engraftment.…”

Section: Gfi1 Added To the Ggf Cocktail Expands The Derived Hspc Poolmentioning

confidence: 99%

“…To avoid both reprogramming to pluripotency and altering the p53 network of the reprogrammed cells, these cocktails were not used further. In-house developed software 'GPSforGenes' [30] shows that the TF combinations for GGF and 3GF, as well as GATA2 + FOS or GATA2 + GFI1 + FOS, were all highly expressed both in CD34 + hematopoietic stem progenitor cells (HSPCs) and placental tissue (Fig. 1C).…”

Section: Gfi1 Added To the Ggf Cocktail Expands The Derived Hspc Poolmentioning

confidence: 99%

“…During reprogramming, the transduced cells appear to traverse from an endothelial precursor and then undergo an EHT to yield clonogenic progenitors [29]. We have transferred these findings to the human system and found that GGF reprogrammed fibroblasts appear to undergo the same type of process and can develop into short-term repopulating cells [30]. These cells gave rise to engraftable hematopoietic cells after maturation demonstrating that in vitro reprogramming can inform normal hematopoiesis [34].…”

mentioning

confidence: 93%

“…Ectopic TF overexpression to alter cell identity translated to the field of hematopoiesis, and multiple studies used different starting mouse or human cell populations, TF combinations, or culture conditions to obtain various types of in vitro derived blood products de novo [11,12]. Several of these studies focused on using either pluripotent [17][18][19][20][21][22][23][24] or somatic [25][26][27][28][29][30] cells with varying levels of success. Encouragingly, recent studies obtained transplantable cells using either human iPSCs [31] or human/mouse endothelial cells with a vascular niche coculture system [32,33].…”

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confidence: 99%

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Induction of human hemogenesis in adult fibroblasts by defined factors and hematopoietic coculture

et al. 2019

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Transcription factor (TF)‐based reprogramming of somatic tissues holds great promise for regenerative medicine. Previously, we demonstrated that the TFs GATA2, GFI1B, and FOS convert mouse and human fibroblasts to hemogenic endothelial‐like precursors that generate hematopoietic stem progenitor (HSPC)‐like cells over time. This conversion is lacking in robustness both in yield and biological function. Herein, we show that inclusion of GFI1 to the reprogramming cocktail significantly expands the HSPC‐like population. AFT024 coculture imparts functional potential to these cells and allows quantification of stem cell frequency. Altogether, we demonstrate an improved human hemogenic induction protocol that could provide a valuable human in vitro model of hematopoiesis for disease modeling and a platform for cell‐based therapeutics. Database Gene expression data are available in the Gene Expression Omnibus (GEO) database under the accession number http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE130361.

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Section: Rnaseq Analysismentioning

confidence: 99%

Section: Gfi1 Added To the Ggf Cocktail Expands The Derived Hspc Poolmentioning

confidence: 99%

Section: Gfi1 Added To the Ggf Cocktail Expands The Derived Hspc Poolmentioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

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Induction of human hemogenesis in adult fibroblasts by defined factors and hematopoietic coculture

et al. 2019

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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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The hemogenic endothelium: a critical source for the generation of PSC-derived hematopoietic stem and progenitor cells

Lange

Morgan

Schambach

2021

Cell. Mol. Life Sci.

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In vitro generation of hematopoietic cells and especially hematopoietic stem cells (HSCs) from human pluripotent stem cells (PSCs) are subject to intensive research in recent decades, as these cells hold great potential for regenerative medicine and autologous cell replacement therapies. Despite many attempts, in vitro, de novo generation of bona fide HSCs remains challenging, and we are still far away from their clinical use, due to insufficient functionality and quantity of the produced HSCs. The challenges of generating PSC-derived HSCs are already apparent in early stages of hemato-endothelial specification with the limitation of recapitulating complex, dynamic processes of embryonic hematopoietic ontogeny in vitro. Further, these current shortcomings imply the incompleteness of our understanding of human ontogenetic processes from embryonic mesoderm over an intermediate, specialized hemogenic endothelium (HE) to their immediate progeny, the HSCs. In this review, we examine the recent investigations of hemato-endothelial ontogeny and recently reported progress for the conversion of PSCs and other promising somatic cell types towards HSCs with the focus on the crucial and inevitable role of the HE to achieve the long-standing goal—to generate therapeutically applicable PSC-derived HSCs in vitro.

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Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming

Cited by 30 publications

References 62 publications

Induction of human hemogenesis in adult fibroblasts by defined factors and hematopoietic coculture

Induction of human hemogenesis in adult fibroblasts by defined factors and hematopoietic coculture

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

The hemogenic endothelium: a critical source for the generation of PSC-derived hematopoietic stem and progenitor cells

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