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Direct conversion of human fibroblasts to multilineage blood progenitors

ABSTRACT: Similar to embryo-derived stem cells, application of human induced pluripotent stem cells (iPSCs) is limited by our understanding of lineage specification. Here, we demonstrate the ability to generate progenitors and mature cells of the hematopoietic fate directly from human dermal fibroblasts without establishing pluripotency. POU domain activation of hematopoietic transcription factors by ectopic expression of Oct-4, together with specific cytokine treatment, allowed generation of cells expressing the pan-leukocyte marker CD45. These unique fibroblast-derived cells gave rise to granulocytic, monocytic, megakaryocytic, and erythroid lineages, and demonstrated in vivo engraftment capacity. Distinct from PSC-derived hematopoietic cells, adult and not embryonic hematopoietic programs are activated, consistent with bypassing pluripotent state to generate blood fate. These findings suggest an alternative approach to cellular reprogramming for autologous cell-replacement therapies that avoids complications associated with the use of human PSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE24621 | GEO | 2010/10/20

SECONDARY ACCESSION(S): PRJNA132443

REPOSITORIES: GEO

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Direct conversion of human fibroblasts to multilineage blood progenitors

Project description:Similar to embryo-derived stem cells, application of human induced pluripotent stem cells (iPSCs) is limited by our understanding of lineage specification. Here, we demonstrate the ability to generate progenitors and mature cells of the hematopoietic fate directly from human dermal fibroblasts without establishing pluripotency. POU domain activation of hematopoietic transcription factors by ectopic expression of Oct-4, together with specific cytokine treatment, allowed generation of cells expressing the pan-leukocyte marker CD45. These unique fibroblast-derived cells gave rise to granulocytic, monocytic, megakaryocytic, and erythroid lineages, and demonstrated in vivo engraftment capacity. Distinct from PSC-derived hematopoietic cells, adult and not embryonic hematopoietic programs are activated, consistent with bypassing pluripotent state to generate blood fate. These findings suggest an alternative approach to cellular reprogramming for autologous cell-replacement therapies that avoids complications associated with the use of human PSCs. Molecular analysis was done on purified untransduced Fibs, Oct-4 transduced Fibs at day 4, CD45+ve Fibs at day 21 and hematopoietic cytokine treated CD45+ve Fibs at day 37. The day 4 Oct-4 transduced Fibs were isolated by puromycin selection overnight (Oct-4 vector contains puromycin resistance cassette), purity of sample was validated by staining for Oct-4 followed by Oct-4 expression analysis using flow cytometry; samples used for molecular analysis exhibited 99% Oct-4 levels. The day 21 and day 37 CD45+veFibsOct-4 were isolated based on their CD45 expression. D21 and D37 cells were stained with CD45-APC antibody (BD Biosciences) and sorted using FACSAria II (Becton- Dickinson); samples used for molecular analysis exhibited 99% CD45 levels. Analysis was performed on two biological replicates per sample.

2010-10-20 | E-GEOD-24621 | biostudies-arrayexpress

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Project description:Advances in molecular strategies to reprogram cell fate is a promising avenue for cell-based therapies. Methods to generate induced neural stem cells (iNSCs) are often slow with limited reprogramming events and it is unclear whether cells transit via a pluripotent state. We report an iNSC reprogramming approach from embryonic and aged mouse fibroblasts using an engineered Sox17 (eSox17FNV). eSox17FNV efficiently drives iNSC reprogramming while Sox2 or Sox17 fails to do so. eSox17FNV acquires the capacity to bind new protein partners to scan the genome more efficiently and possesses a more potent transactivation domain than Sox2. At the onset of reprogramming, in the presence of eSox17FNV, fibroblasts divert from a iPSC route towards iNSC fate. Further, lineage tracing shows that emerging iNSCs do not transit through a pluripotent state if POU factors are excluded. This reveals new molecular and physiological framework for iNSC generation and contrasts with lineage from pluripotency reprogramming.

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An engineered Sox17 induces somatic to neural stem cell fate transition independently from pluripotency reprogramming [RNA-seq]

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An engineered Sox17 induces somatic to neural stem cell fate transition independently from pluripotency reprogramming [RNA-seq III]

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An engineered Sox17 induces somatic to neural stem cell fate transition independently from pluripotency reprogramming [RNA-seq II]

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An engineered Sox17 induces somatic to neural stem cell fate transition independently from pluripotency reprogramming [scRNA-seq]

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An engineered Sox17 induces somatic to neural stem cell fate transition independently from pluripotency reprogramming [RRBS]

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