Hematopoiesis from Multipotent Stem Cells


Pathway Description

Hematopoiesis, the process of generation of blood cells, begins in the early embryo and continues throughout life. It involves the generation of blood cells of various lineages. Hematopoietic stem cells (HSCs) are classified into long-term, short-term and multipotent progenitors based on the extent of their self-renewal abilities. The intricate, finely tuned regulatory pathways that control both basal and emergency hematopoiesis are mediated largely by cytokines and their cognate receptors. As most mature blood cells are short-lived, new blood cells continually arise from multipotent HSCs. In addition to maintaining steady-state hematopoiesis, the system also responds to physiological stresses, such as bleeding or infection. Cytokines of the hematopoietic system broadly include interleukins, CSFs, IFNs, EPO and TPO.

Blood cell development progresses from HSC to either self-renewal or differentiation into multilineage committed progenitor cells, namely common lymphoid progenitor cells (CLP) or common myeloid progenitor cells (CMP). These progenitor cells then give rise to differentiated progenitors comprising lineages that include T-cell and natural killer cell progenitor cells (TNK), granulocyte and macrophage progenitor cells (GMP), and megakaryocyte and erythroid progenitor cells (MEP). Ultimately, these cells give rise to unilineage committed progenitors for B cells, NK cells, T cells, granulocytes (neutrophils, eosinophils, basophils), monocytes/macrophages/dendritic cells, erythrocytes and megakaryocytes.

Each step of hematopoietic progression - survival, proliferation or differentiation is well supported by cytokines and growth factors such as SCF, TPO, IL-7, IL-3, GMCSF, EPO, IL-2, IL-4, IL-5 and M-CSF. During the initial stages of hematopoietic cell development, IL-7 initiates CLP formation whereas SCF, TPO and SCF regulate CMP proliferation from HSCs. CMP differentiate into MEP and GMP. Later the megakaryocytic and erythroid progenitors are primarily regulated by TPO and EPO. The more lineage restricted cytokines such as M-CSF and GMCSF regulate monocytic and granulocytic lineages, respectively. GCSF, IL-5, SCF and IL-3 are important in the development of eosinophils, SCF for basophils or mast cells and GCSF for neutrophils. IL-7 regulates the differentiation of CLP into TNK and B-cell progenitor cells (BCP), initiating the lymphocytic lineage development processes. The TNKs then differentiate into TCP (via IL-2 and IL-7) and NKP (via IL-7), whereas IL-4 is crucial for differentiation of BCP into B cells.