Hemopoietic stem cells

\\i hsbr takrn this essay from this article in Seminars in Immunology

The differentiation of hematopoietic stem cells into the wide spectrum of mature blood cells is a well orchestrated and regulated process, controlled in large part by distinct sets of transcription factors. All of the cells of the immune system and all blood cells are derived from the long-term hematopoietic stem cell (LT-HSC). In the bone marrow, LT-HSCs have the ability to both self-renew and reconstitute the entire immune system as well as all blood cells for the life of the organism. LT-HSCs can differentiate into short-term hematopoietic stem cells (ST-HSCs), which also maintain multipotency, but only have self-renewal capability for a limited time. ST-HSCs then differentiate into multipotent progenitors (MPPs), which are multipotent, but lack self-renewal capability. HSCs and MPPs express transcription factors from multiple lineages, commonly referred to as lineage priming.

This priming represents the developmental plasticity of early hematopoietic progenitors. Upon instructive cytokine signaling, the multipotent progenitors sequentially modulate the expression of genes encoding transcription factors that, in turn, activate the expression of lineage-specific genes and antagonize programs of gene expression associated with alternative cell lineages.

Symmetric, self-renewing divisions of LT-HSCs occur rapidly in fetal development to ensure proper seeding of blood and immune compartments. However, in adults, LT-HSCs are often found in quiescent, not in dividing states. The self-renewal capability of these cells is maintained through complex regulation of multiple pathways, including the Notch and Wnt signaling pathways, Hox transcription factors, and the cell cycle regulators INK4A, INK4C, p21, p27, and PTEN. LT-HSCs are identified through the absence of cell surface markers of differentiated immune cells (lineage negative), and the presence of cKit, Sca1 (LSK), and CD150. Downregulation of CD150 marks differentiation into the ST-HSC and MPP, and a subsequent decline of self-renewal activity. Differentiation from the MPP into more committed progenitors was previously thought to proceed through a bifurcated pathway, with the B, T and natural killer (NK) cell lineages developing from the common lymphoid progenitor (CLP) and the monocyte, granulocyte, megakaryocyte and erythroid lineages from the common myeloid progenitor (CMP). This roadmap has been revised in recent years to include lymphoid primed multipotent progenitor (LMPP). In this scenario, MPPs have the ability to differentiate into the erythroid or megakaryocyte lineage through a pre-megakaryocyte/erythroid progenitor (MEP), which expresses low to intermediate levels of CD105 and CD34 and low levels of CD41, or into the lymphoid/myeloid lineage through the LMPP, which is characterized by high levels of Flt3. While the MEP is restricted to a megakaryoctye or erythroid lineage, the LMPP has potential for B, T, NK, monocyte, and granulocyte lineages. Antagonistic activities of the transcription factors GATA-1 and PU.1 effectively segregate the MEP from LMPP lineages, with GATA-1 directing development into MEPs and PU.1 promoting the LMPP fate.

Expression and signaling through the Flt3 tyrosine kinase receptor in LMPPs favors differentiation into the B or T lymphoid lineages. The LMPP generates the lymphoid lineages through either an early T-cell progenitor (ETP) or a common lymphoid progenitor (CLP), or both. From the Lin−Sca low, ckit low, Flt3 high, IL7R high CLP, early B-cell development proceeds through an ordered pathway beginning with the Ly6D positive B-primed lymphoid progenitor (BLP), then into a B220 int CD4 3high pre-pro-B cell, a B220 high CD19 high pro-B cell, and finally into the CD25 positive pre-B cell. Many of these early lineages are defined based on rearrangement of the antigen receptor genes IgH, IgK and IgL. Rearrangement of the D-J fragments of the IgH gene has been documented as early as the CLP stage. Upon expression of CD19 at the pro-B cell stage, V-DJ rearrangement of IgH has been completed. Upon expression of the pre-B cell receptor, the cells then proliferate and differentiate to a CD25 positive pre-B cell stage, where rearrangement of the BCR light chain is initiated.

T lineage specification arises through a Lin−ckit+CD44+CD25− ETP or double negative 1 (DN1) bone marrow derived thymic progenitor. ETPs, previously thought to be committed to the T-cell lineage, actually maintain myeloid, dendritic, and natural killer (NK) cell potential as shown by both in vitro and in vivo differentiation assays. T cell progression proceeds from the DN1 to a Lin−ckit+CD44+CD25+ DN2, a Lin−ckit−CD44−CD25+ DN3 and a Lin−ckit−CD44−CD25− DN4 cell. Recently, the DN2 stage has been subdivided into DN2a and DN2b on the basis of the expression of the T cell commitment factor, Bcl11b, and the DN3 stage has been subdivided into DN3a and DN3b on the basis of CD27 expression. Full commitment to the T lineage occurs at the DN3a stage. To proceed through the DN3 stage of commitment, burgeoning T cells must progress through a T cell receptor (TCR) checkpoint, where the cell must successfully rearrange and express either the TCR-β and pre-Tα genes, or the γ and δ TCR loci. Expression of the TCR-β and pre-Tα genes, known as the pre-TCR, directs T cells to rapidly divide and differentiate to the CD4+CD8+ double positive (DP) stage of T cell development. It is during this stage that the pre-TCR signals to rearrange the TCR Vα and Jα segments to complete mature TCR expression.From the DP compartment, T cells proceed to a CD4 or CD8 single positive stage before exiting the thymus.

The myeloid lineage develops through granulocyte-macrophage progenitors (GMPs), which can arise from either the LMPP or MPP compartments. LMPPs differentiate into the myeloid lineage through the FcγR positive granulocyte/macrophage progenitor (GMP), or into the lymphoid lineage through the IL7R positive common lymphoid progenitor (CLP). The GMP can be isolated based on cell surface expression of FCγR and CD34 within the LSK CD4 low progenitor fraction. Further signaling through the macrophage colony stimulating factor receptor (MCSFR) or granulocyte-CSFR (GCSFR) by G-CSF, M-CSF and/or GM-CSF leads to changes in transcription factor expression and the delineation of the neutrophil or macrophage fate. Macrophages or neutrophils are specified from the GMP based on interactions of PU.1 with the CCAAT/enhancer binding proteins (CEBPα, β, and ɛ), with high levels of the CEBPs defining granulopoiesis and high levels of PU.1 inducing macrophage development.