Open AccessHhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation
Author(s) -
Goodings Charnise,
Smith Elizabeth,
Mathias Elizabeth,
Elliott Natalina,
Cleveland Susan M.,
Tripathi Rati M.,
Layer Justin H.,
Chen Xi,
Guo Yan,
Shyr Yu,
Hamid Rizwan,
Du Yang,
Davé Utpal P.
Publication year - 2015
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2049
Subject(s) - biology , stem cell , progenitor cell , haematopoiesis , microbiology and biotechnology , hematopoietic stem cell , conditional gene knockout , embryonic stem cell , bone marrow , transplantation , cellular differentiation , immunology , cancer research , genetics , medicine , phenotype , gene
Hhex encodes a homeodomain transcription factor that is widely expressed in hematopoietic stem and progenitor cell populations. Its enforced expression induces T‐cell leukemia and we have implicated it as an important oncogene in early T‐cell precursor leukemias where it is immediately downstream of an LMO2‐associated protein complex. Conventional Hhex knockouts cause embryonic lethality precluding analysis of adult hematopoiesis. Thus, we induced highly efficient conditional knockout (cKO) using vav‐Cre transgenic mice. Hhex cKO mice were viable and born at normal litter sizes. At steady state, we observed a defect in B‐cell development that we localized to the earliest B‐cell precursor, the pro‐B‐cell stage. Most remarkably, bone marrow transplantation using Hhex cKO donor cells revealed a more profound defect in all hematopoietic lineages. In contrast, sublethal irradiation resulted in normal myeloid cell repopulation of the bone marrow but markedly impaired repopulation of T‐ and B‐cell compartments. We noted that Hhex cKO stem and progenitor cell populations were skewed in their distribution and showed enhanced proliferation compared to WT cells. Our results implicate Hhex in the maintenance of LT‐HSCs and in lineage allocation from multipotent progenitors especially in stress hematopoiesis. S tem C ells 2015;33:2628—2641