Reduced lymphoid lineage priming promotes human hematopoietic stem cell expansion.
Cell Stem Cell, 2014/1/02;14(1):94-106.
van Galen P[1], Kreso A[2], Wienholds E[1], Laurenti E[1], Eppert K[3], Lechman ER[1], Mbong N[1], Hermans K[1], Dobson S[2], April C[4], Fan JB[4], Dick JE[5]
Affiliations
PMID: 24388174
Impact factor: 25.269
Abstract
The hematopoietic system sustains regeneration throughout life by balancing self-renewal and differentiation. To stay poised for mature blood production, hematopoietic stem cells (HSCs) maintain low-level expression of lineage-associated genes, a process termed lineage priming. Here, we modulated expression levels of Inhibitor of DNA binding (ID) proteins to ask whether lineage priming affects self-renewal of human HSCs. We found that lentiviral overexpression of ID proteins in cord blood HSCs biases myeloerythroid commitment at the expense of lymphoid differentiation. Conversely, reducing ID2 expression levels increases lymphoid potential. Mechanistically, ID2 inhibits the transcription factor E47 to attenuate B-lymphoid priming in HSCs and progenitors. Strikingly, ID2 overexpression also results in a 10-fold expansion of HSCs in serial limiting dilution assays, indicating that early lymphoid transcription factors antagonize human HSC self-renewal. The relationship between lineage priming and self-renewal can be exploited to increase expansion of transplantable human HSCs and points to broader implications for other stem cell populations.
MeSH terms
Animals; Biomarkers; Blotting, Western; Cell Differentiation; Cell Lineage; Cell Proliferation; Cells, Cultured; Fetal Blood; Gene Expression Profiling; Hematopoietic Stem Cells; Humans; Inhibitor of Differentiation Protein 2; Lymphocytes; Male; Mice; Mice, Inbred NOD; Mice, SCID; Myeloid Cells; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factor 3; Transplantation, Heterologous
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