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Reprogramming mouse fibroblasts into engraftable myeloerythroid and lymphoid progenitors

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ABSTRACT

Recent efforts have attempted to convert non-blood cells into hematopoietic stem cells (HSCs) with the goal of generating blood lineages de novo. Here we show that hematopoietic transcription factors Scl, Lmo2, Runx1 and Bmi1 can convert a developmentally distant lineage (fibroblasts) into ‘induced hematopoietic progenitors' (iHPs). Functionally, iHPs generate acetylcholinesterase+ megakaryocytes and phagocytic myeloid cells in vitro and can also engraft immunodeficient mice, generating myeloerythoid and B-lymphoid cells for up to 4 months in vivo. Molecularly, iHPs transcriptionally resemble native Kit+ hematopoietic progenitors. Mechanistically, reprogramming factor Lmo2 implements a hematopoietic programme in fibroblasts by rapidly binding to and upregulating the Hhex and Gfi1 genes within days. Moreover the reprogramming transcription factors also require extracellular BMP and MEK signalling to cooperatively effectuate reprogramming. Thus, the transcription factors that orchestrate embryonic hematopoiesis can artificially reconstitute this programme in developmentally distant fibroblasts, converting them into engraftable blood progenitors.

No MeSH data available.


Model of hematopoietic reprogramming.Scl, Lmo2, Runx1 might act as ‘lineage commitment' regulators whereas Bmi1 or Hoxb4 might be ‘self-renewal' factors in HSC development. The hematopoietic reprograming activity of these transcription factors also jointly requires extracellular signals mediated through the BMP and MEK cascades. Finally, Lmo2 activates other hematopoietic transcription factors (for example, Gfi1 and Hhex) to drive iHP reprogramming.
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f8: Model of hematopoietic reprogramming.Scl, Lmo2, Runx1 might act as ‘lineage commitment' regulators whereas Bmi1 or Hoxb4 might be ‘self-renewal' factors in HSC development. The hematopoietic reprograming activity of these transcription factors also jointly requires extracellular signals mediated through the BMP and MEK cascades. Finally, Lmo2 activates other hematopoietic transcription factors (for example, Gfi1 and Hhex) to drive iHP reprogramming.

Mentions: Altogether the sequential transcriptional code we have identified for hematopoietic reprogramming is evocative of some aspects of hematopoietic development: Scl and Lmo2 may be minimally sufficient to implement a hematopoietic fate (as evinced during embryogenesis), though we find that the numbers and engraftability of iHPs produced in this fashion are augmented by addition of Runx1 together with Bmi1, which might be reprising some of their roles as hematopoietic specification factors and self-renewal factors, respectively (Fig. 8). This type of a developmental transcriptional logic for lineage reprogramming may parallel what is seen for the conversion of adult mouse exocrine cells to β-cells, which involves three transcription factors (Pdx1, Ngn3 and MafA), which during embryogenesis serve to respectively induce pancreatic progenitors, then endocrine precursors and specifically β-cells55. Therefore ontogenic insights into how specific fates are programmed during development may reciprocally benefit how these fates can be reprogrammed from other lineages in artificial contexts.


Reprogramming mouse fibroblasts into engraftable myeloerythroid and lymphoid progenitors
Model of hematopoietic reprogramming.Scl, Lmo2, Runx1 might act as ‘lineage commitment' regulators whereas Bmi1 or Hoxb4 might be ‘self-renewal' factors in HSC development. The hematopoietic reprograming activity of these transcription factors also jointly requires extracellular signals mediated through the BMP and MEK cascades. Finally, Lmo2 activates other hematopoietic transcription factors (for example, Gfi1 and Hhex) to drive iHP reprogramming.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121332&req=5

f8: Model of hematopoietic reprogramming.Scl, Lmo2, Runx1 might act as ‘lineage commitment' regulators whereas Bmi1 or Hoxb4 might be ‘self-renewal' factors in HSC development. The hematopoietic reprograming activity of these transcription factors also jointly requires extracellular signals mediated through the BMP and MEK cascades. Finally, Lmo2 activates other hematopoietic transcription factors (for example, Gfi1 and Hhex) to drive iHP reprogramming.
Mentions: Altogether the sequential transcriptional code we have identified for hematopoietic reprogramming is evocative of some aspects of hematopoietic development: Scl and Lmo2 may be minimally sufficient to implement a hematopoietic fate (as evinced during embryogenesis), though we find that the numbers and engraftability of iHPs produced in this fashion are augmented by addition of Runx1 together with Bmi1, which might be reprising some of their roles as hematopoietic specification factors and self-renewal factors, respectively (Fig. 8). This type of a developmental transcriptional logic for lineage reprogramming may parallel what is seen for the conversion of adult mouse exocrine cells to β-cells, which involves three transcription factors (Pdx1, Ngn3 and MafA), which during embryogenesis serve to respectively induce pancreatic progenitors, then endocrine precursors and specifically β-cells55. Therefore ontogenic insights into how specific fates are programmed during development may reciprocally benefit how these fates can be reprogrammed from other lineages in artificial contexts.

View Article: PubMed Central - PubMed

ABSTRACT

Recent efforts have attempted to convert non-blood cells into hematopoietic stem cells (HSCs) with the goal of generating blood lineages de novo. Here we show that hematopoietic transcription factors Scl, Lmo2, Runx1 and Bmi1 can convert a developmentally distant lineage (fibroblasts) into ‘induced hematopoietic progenitors' (iHPs). Functionally, iHPs generate acetylcholinesterase+ megakaryocytes and phagocytic myeloid cells in vitro and can also engraft immunodeficient mice, generating myeloerythoid and B-lymphoid cells for up to 4 months in vivo. Molecularly, iHPs transcriptionally resemble native Kit+ hematopoietic progenitors. Mechanistically, reprogramming factor Lmo2 implements a hematopoietic programme in fibroblasts by rapidly binding to and upregulating the Hhex and Gfi1 genes within days. Moreover the reprogramming transcription factors also require extracellular BMP and MEK signalling to cooperatively effectuate reprogramming. Thus, the transcription factors that orchestrate embryonic hematopoiesis can artificially reconstitute this programme in developmentally distant fibroblasts, converting them into engraftable blood progenitors.

No MeSH data available.