Hematopoiesis from Pluripotent Stem Cells

Hematopoietic Stem Cells (HSC) have the property of self-renewal, and through cell division and differentiation, form populations of progenitor cells which are committed to the main marrow cell lineages, including erythroid, granulocytic, monocytic, megakaryocytic and lymphocytic lineages. The initial stages of pluripotent hematopoietic cell development are regulated by broadly acting cytokines such as IL-3, SCF, GM-CSF, IL-1, IL-6, IL-11 and IL-2. The various progenitor cells are identified by the type of colony they form. In culture media, the progenitor cells are defined as colony-forming units (CFU). The earliest detectable hematopoietic progenitor cell that gives rise to granulocytes, erythroblasts, monocytes and megakaryocytes is termed CFU-GEMM. Physiological regulation of myeloid stem cell into CFU-GEMM is mediated by IL-3, IL-6, IL-1, SCF, GM-CSF and IL-12. CFU-GEMM mature into more specialized precursor cells termed as CFU-GM/CFU-C, CFU-Eo, CFU-Bas, CFU-Mast/CFU-MC, CFU-E and CFU-Meg/CFU-Mk. The burst-forming units, BFU-E and BFU-Meg/BFU-Mk are earlier erythroid progenitors of CFU-E and CFU-Meg, respectively. During erythroid developmental progression from BFU-E, IL-3, GM-CSF and EPO have a profound stimulatory effect on precursor cells at various stages. Likewise, during the process of megakaryocytopoiesis from BFU-Meg, IL-3, GM-CSF and TPO act as regulators of the megakaryocytic lineage, while IL-6 stimulates the formation of platelets from megakaryocytes. CFU-Mast differentiates into mast cells after cell activation in response to SCF and IL-3. The basophilic differentiation from CFU-Bas requires IL-3, IL-4 and GM-CSF as modulators. CD34+ cells that express receptors for IL-3, IL-4, IL-5 and GM-CSF are considered eosinophil/basophil progenitors. Myeloid stem cell differentiation into granulocyte progenitors is promoted by IL-3, GM-CSF and G-CSF that give rise to CFU-G and CFU-M. CFU-G ultimately mature into polymorpho-nucleated neutrophils.Lymphoid stem cells, on the other hand, give rise to B cell, T cell, and NK cell lineages. IL-1, IL-2, IL-6, IL-7 and SCF act on multipotential lymphoid stem cells which further differentiate into specific B cell and T cell progeny. Depending on TCR gene arrangements, T cell progenitor cells develop into T cells with TCRγ/TCRδ receptors or with TCRα/TCRβ receptors. The lineage committed T cell progenitors give rise to Th cells and Tc cells. All Th cells are CD4+ and all Tc cells are CD8+. The process of Th cell differentiation further gives rise to Th cell subsets such as Treg, Th1, Th2 and Th17, whereas antigen stimulation leads to development of memory T cells. Similarly, cytokines are also crucial for development of B cell progeny. The lymphoid stem cells first develop into B cell progenitor cells (BCP). BCP give rise to pro B cells which develop into mature B cells, with IgM or IgD as surface receptors. Cytokines such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IFNγ and TGFβ regulate isotype switch signals that differentiate mature B cells into plasma cells, IgM antibody secreting B cells and memory B cells. Billions of new blood cells are produced in the body on a daily basis, with each one derived from a single hematopoietic stem cell.