Reprogramming human endothelial cells to haematopoietic cells requires vascular induction

Sandler, Vladislav M.; Lis, Raphaël; Liu, Ying; Kedem, Alon; James, Daylon; Elemento, Olivier; Butler, Jason M.; Scandura, Joseph M.; Rafii, Shahin

doi:10.1038/nature13547

Cited by 207 publications

(216 citation statements)

References 43 publications

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“…Finally, much effort in the field is directed at deriving transplantable HSCs from other cells types, via differentiation of induced pluripotent stem cells, 69 transdifferentiation of somatic cells such as fibroblasts 70 and endothelial cells, 71 and also reprogramming/respecification of committed blood cells. 72 Ultimately, the success of such efforts is contingent on instating (in the case of directed differentiation or transdifferentiation) or reinstating (in the case of reprogramming from differentiated blood cells) the regulatory networks governing HSC potential onto these other cell types.…”

Section: Discussionmentioning

confidence: 99%

Regulatory network control of blood stem cells

Göttgens

2015

Blood

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Hematopoietic stem cells (HSCs) are characterized by their ability to execute a wide range of cell fate choices, including selfrenewal, quiescence, and differentiation into the many different mature blood lineages. Cell fate decision making in HSCs, as indeed in other cell types, is driven by the interplay of external stimuli and intracellular regulatory programs. Given the pivotal nature of HSC decision making for both normal and aberrant hematopoiesis, substantial research efforts have been invested over the last few decades into deciphering some of the underlying mechanisms. Central to the intracellular decision making processes are transcription factor proteins and their interactions within gene regulatory networks. More than 50 transcription factors have been shown to affect the functionality of HSCs. However, much remains to be learned about the way in which individual factors are connected within wider regulatory networks, and how the topology of HSC regulatory networks might affect HSC function. Nevertheless, important progress has been made in recent years, and new emerging technologies suggest that the pace of progress is likely to accelerate. This review will introduce key concepts, provide an integrated view of selected recent studies, and conclude with an outlook on possible future directions for this field. (Blood. 2015;125(17):2614-2620 Building blocks of transcriptional regulatory networksThe primary components of transcriptional regulatory networks are transcription factor (TF) proteins and the gene regulatory DNA sequences that they bind to.1 By binding to specific DNA sequence motifs within gene regulatory regions, TF proteins are central players for this primary step of decoding gene regulatory instructions. TF proteins typically contain a number of distinct modules, such as DNA binding, transcriptional activation, and protein/protein interaction domains, with the latter 2 being essential for the recruitment of the basal transcriptional machinery and the assembly of higherorder TF complexes. Based on sequence similarity within the DNA binding domain, TF proteins can be categorized into distinct families, such as homeobox, basic helix-loop-helix, or zinc finger TFs. Members of a given TF family often bind to similar DNA sequences, and proteinprotein interactions are common both within and between the different TF families.Individual TFs bind short sequence motifs that are often no longer than 4 to 6 bp. Any given 6-bp sequence will occur on average approximately once every 4000 bp. Consequently, there will be ;750 000 occurrences just by chance within the 3 000 000 000 bp of the human genome. The number of possible binding sites therefore far exceeds the 20 000 or so human genes, and it has long been assumed that only a small minority of all motif instances play a role in transcriptional regulation. Functional gene regulatory regions should therefore display characteristics that go beyond the mere occurrence of a specific sequence motif. One such characteristic is the presence of clusters of b...

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Section: Discussionmentioning

confidence: 99%

Regulatory network control of blood stem cells

Göttgens

2015

Blood

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“…These studies spawned quests for combinations of transcription factors, overexpression of which could generate clinically relevant cell types, including HSCs. Groups chose either ESCs (Kyba et al, 2002;Elcheva et al, 2014), human endothelial cells (Sandler et al, 2014), haematopoietic cells or fibroblasts Batta et al, 2014) as the starting material. Comparative transcriptomics of HSC and progenitor cell populations often provided lists of candidate factors to overexpress.…”

Section: Direct Cell Lineage Conversion: Programming and Reprogramminmentioning

confidence: 99%

“…Indeed, it may be for this reason that efforts to generate bona fide HSCs from PSCs in vitro have not been successful, undermining expectations for the generation of HSCs for clinical needs. This, in turn, has stimulated the quest for alternative methodologies, such as direct cell reprogramming (Riddell et al, 2014;Sandler et al, 2014). In this Review, we first discuss in vivo human haematopoietic development, focussing on the different anatomical sites where haematopoiesis takes place, as well as the molecular and functional characterisation of human haematopoietic stem and progenitor cells as they emerge in a spatiotemporal manner.…”

Section: Introductionmentioning

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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“…A supply of healthy cells capable of contributing to tissue repair and regeneration without risk of host rejection or malignant transformation is vital to achieving this goal. In this regard, bone marrow transplantation and skin and bone grafts have proven clinical utility (1)(2)(3)(4). However, for the majority of tissues that require regeneration, harvesting and expanding stem and progenitor cells is a challenge, and tissue grafting is not an option due to siteand tissue-specific limitations.…”

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confidence: 99%

PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells

Chandrakanthan

Yeola

Kwan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Current approaches in tissue engineering are geared toward generating tissue-specific stem cells. Given the complexity and heterogeneity of tissues, this approach has its limitations. An alternate approach is to induce terminally differentiated cells to dedifferentiate into multipotent proliferative cells with the capacity to regenerate all components of a damaged tissue, a phenomenon used by salamanders to regenerate limbs. 5-Azacytidine (AZA) is a nucleoside analog that is used to treat preleukemic and leukemic blood disorders. AZA is also known to induce cell plasticity. We hypothesized that AZA-induced cell plasticity occurs via a transient multipotent cell state and that concomitant exposure to a receptive growth factor might result in the expansion of a plastic and proliferative population of cells. To this end, we treated lineage-committed cells with AZA and screened a number of different growth factors with known activity in mesenchyme-derived tissues. Here, we report that transient treatment with AZA in combination with platelet-derived growth factor–AB converts primary somatic cells into tissue-regenerative multipotent stem (iMS) cells. iMS cells possess a distinct transcriptome, are immunosuppressive, and demonstrate long-term self-renewal, serial clonogenicity, and multigerm layer differentiation potential. Importantly, unlike mesenchymal stem cells, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner and, unlike embryonic or pluripotent stem cells, do not form teratomas. Taken together, this vector-free method of generating iMS cells from primary terminally differentiated cells has significant scope for application in tissue regeneration.

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Reprogramming human endothelial cells to haematopoietic cells requires vascular induction

Cited by 207 publications

References 43 publications

Regulatory network control of blood stem cells

Regulatory network control of blood stem cells

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

PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells

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