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Directed Differentiation of Primitive and Definitive Hematopoietic Progenitors from Human Pluripotent Stem Cells
Published on: November 1, 2017
miR-143/145 differentially regulate hematopoietic stem and progenitor activity through suppression of canonical TGFβ
Jeffrey Lam1,2, Marion van den Bosch1,2, Joanna Wegrzyn1,2
1Michael Smith Genome Sciences Centre, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.
Abstract:
Expression of miR-143 and miR-145 is reduced in hematopoietic stem/progenitor cells (HSPCs) of myelodysplastic syndrome patients with a deletion in the long arm of chromosome 5. Here we show that mice lacking miR-143/145 have impaired HSPC activity with depletion of functional hematopoietic stem cells (HSCs), but activation of progenitor cells (HPCs). We identify components of the transforming growth factor β (TGFβ) pathway as key targets of miR-143/145. Enforced expression of the TGFβ adaptor protein and miR-145 target, Disabled-2 (DAB2), recapitulates the HSC defect seen in miR-143/145-/- mice. Despite reduced HSC activity, older miR-143/145-/- and DAB2-expressing mice show elevated leukocyte counts associated with increased HPC activity. A subset of mice develop a serially transplantable myeloid malignancy, associated with expansion of HPC. Thus, miR-143/145 play a cell context-dependent role in HSPC function through regulation of TGFβ/DAB2 activation, and loss of these miRNAs creates a preleukemic state.
Insights
MicroRNAs miR-143 and miR-145 are crucial for hematopoietic stem/progenitor cell (HSPC) function. Loss of these miRNAs impairs hematopoietic stem cells, promotes progenitor cells, and can lead to preleukemic conditions.
Area of Science:
- Hematology
- Molecular Biology
- Genetics
Background:
- Reduced expression of miR-143 and miR-145 is observed in myelodysplastic syndrome (MDS) patients with chromosome 5q deletion.
- Hematopoietic stem/progenitor cells (HSPCs) are critical for blood cell formation and are affected in MDS.
Purpose of the Study:
- To investigate the role of miR-143/145 in hematopoietic stem/progenitor cell (HSPC) activity and their potential involvement in myelodysplastic syndrome (MDS).
- To identify the molecular targets and pathways regulated by miR-143/145 in hematopoiesis.
Main Methods:
- Generation and analysis of miR-143/145 knockout mice to assess HSPC function.
- Enforced expression of Disabled-2 (DAB2), a target of miR-145, to mimic HSC defects.
- Assessment of hematopoietic stem cell (HSC) and progenitor cell (HPC) activity, leukocyte counts, and transplantability.
Main Results:
- Mice lacking miR-143/145 exhibit impaired HSPC activity, with depleted HSCs but activated HPCs.
- Components of the transforming growth factor β (TGFβ) pathway, including DAB2, were identified as key targets of miR-143/145.
- Enforced DAB2 expression recapitulated the HSC defect observed in miR-143/145 knockout mice.
- Older knockout mice showed elevated leukocyte counts and a subset developed myeloid malignancy, indicating a preleukemic state.
Conclusions:
- miR-143/145 play a context-dependent role in regulating HSPC function through the TGFβ/DAB2 pathway.
- Loss of miR-143/145 contributes to HSC dysfunction and creates a preleukemic environment, offering insights into MDS pathogenesis.
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