Induction of a Hemogenic Program in Mouse Fibroblasts

Pereira, Carlos Filipe; Chang, Betty; Qiu, Jiajing; Niu, Xiaohong; Papatsenko, Dmitri; Hendry, Caroline; Clark, Neil R.; Nomura-Kitabayashi, Aya; Kovacic, Jason C.; Ma’ayan, Avi; Schaniel, Christoph; Lemischka, Ihor R.; Moore, Kateri

doi:10.1016/j.stem.2013.05.024

Cited by 197 publications

(266 citation statements)

References 55 publications

Supporting

Mentioning

252

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

Regulatory network control of blood stem cells

Göttgens

2015

Blood

View full text Add to dashboard Cite

show abstract

“…This is reflected in the difficulty to generate bona fide HSCs de novo from ES/iPS cells [50,85,[91][92][93], or through direct reprogramming [94,95]. This indicates that critical components of EHT, responsible for regulating the hematopoietic nature of these cells are missing in these culture systems and indicate the importance of understanding the cellular, molecular and niche requirements for EHT in vivo.…”

Section: Discussionmentioning

confidence: 99%

A short history of hemogenic endothelium

Swiers

Rode

Azzoni

et al. 2013

Blood Cells, Molecules, and Diseases

View full text Add to dashboard Cite

Definitive hematopoietic cells are generated de novo during ontogeny from a specialized subset of endothelium, the so-called hemogenic endothelium. In this review we give a brief overview of the identification of hemogenic endothelium, explore its links with the HSC lineage, and summarize recent insights into the nature of hemogenic endothelium and the microenvironmental and intrinsic regulators contributing to its transition into blood. Ultimately, a better understanding of the processes controlling the transition of endothelium into blood will advance the generation and expansion of hematopoietic stem cells for therapeutic purposes.

show abstract

“…(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.

View full text Add to dashboard Cite

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.

show abstract

Induction of a Hemogenic Program in Mouse Fibroblasts

Cited by 197 publications

References 55 publications

Regulatory network control of blood stem cells

Regulatory network control of blood stem cells

A short history of hemogenic endothelium

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

Contact Info

Product

Resources

About