Reprogramming Committed Murine Blood Cells to Induced Hematopoietic Stem Cells with Defined Factors

Riddell, Jonah; Gazit, Roi; Garrison, Brian S.; Guo, Guoji; Saadatpour, Assieh; Mandal, Pankaj Kumar; Ebina, Wataru; Volchkov, Pavel; Yuan, Guo‐Cheng; Orkin, Stuart H.; Rossi, Derrick J.

doi:10.1016/j.cell.2014.06.014

Cited by 80 publications

(119 citation statements)

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“…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. A more thorough understanding of HSC regulatory networks undoubtedly has the potential to greatly accelerate such research efforts.…”

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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“…(13), cardiomyocytes (14), and hematopoietic progenitors (15,16)] and human [e.g., cardiomyocytes (17) and blood progenitors (4)] cells have been reported. However, these methods require vectorbased gene transfer and are of low reprogramming efficiency.…”

Section: Significancementioning

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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“…A similar strategy was used for reprogramming murine hematopoietic cells toward transplantable HSC. 26 Although the reprogramming factors needed for conferring HSC properties have not yet reached consensus, this approach may prove to be an alternative method for generating HSC from pluripotent stem cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, recent publications using reprogramming of specified cells are starting to shed light on this issue. [24][25][26] It was recently reported that overexpression of 5 factors in hESC-derived HPC confers short-term engraftment potential to these hESC-derived cells. 24 One of the factors which was required for in vivo engraftment was characterized as MYB.…”

Section: Discussionmentioning

confidence: 99%