Hematopoiesis is the process that generates blood cells of all lineages . The process begins in the early embryo and continues throughout life . Every day, billions of new blood cells are produced in the body, each one derived from a hematopoietic stem cell (HSC). Because most mature blood stem cells have a limited life span, the ability of HSCs to perpetuate themselves through self-renewal and generate new blood cells for the lifetime of an organism is critical to sustaining life. Hematopoietic stem cells are classified into long-term, short-term, and multipotent progenitors, based on the extent of their self-renewal abilities .
A key problem in hematopoietic stem cell biology is how HSC self-renewal is regulated. Signaling cascades like the WNT (Wingless-Type MMTV integration site family) pathway is commonly known to regulate stem cell fate choice in a variety of organs, including the skin, the nervous system, and the hematopoietic system. In the hematopoietic system, stimulation of hematopoietic progenitors and stem cells with soluble WNT proteins or downstream activators of the WNT signaling leads to their expansion . The intricate, finely tuned regulatory pathways that control both basal and emergency hematopoiesis are mediated largely by cytokines and their cognate receptors. Cytokines of the hematopoietic system broadly includes interleukins (ILs), colony-stimulating factors (CSFs), Interferons (IFNs), Erythropoietin (Epo), and Thrombopoietin (Tpo). They bind to a family of cytokine receptors that share a number of features. The receptors can be composed of dimers of a single receptor [Granulocyte Colony-Stimulating Factor Receptor (GCSFR), Erythropoietin Receptor (EpoR), Tpo Receptor, or c-Mpl)] or can be heterodimeric with a common signaling subunit and a unique ligand-binding chain . As most mature blood cells are short-lived, new blood cells continually arise from multipotent HSC and become committed to the erythroid, megakaryocytic, granulocytic, monocytic, and lymphocytic lineages . Models of blood-cell production construct envision hematopoiesis as a hierarchical progression of multipotential HSCs that gradually lose one or more developmental options, becoming progenitor cells committed to a single lineage; these progenitors then mature into the corresponding types of peripheral-blood cells. Blood-cell development progresses from an HSC undergoing either self-renewal or differentiation into a multilineage committed progenitor cell: a common lymphoid progenitor or a CMP common myeloid progenitor (CMP). The CLP and CMP are considered primitive progenitor cells which then give rise to more differentiated progenitors (also termed as committed precursor cells), comprising lineages that include T-cells and natural killer cells (TNKs), granulocytes and macrophages (GMs), and megakaryocytes and erythroid cells (MEPs). Ultimately, these cells give rise to unilineage committed progenitors for B-cells (BCPs); NK cells (NKPs); T-cells (TCPs); granulocytes (GPs) like neutrophils, eosinophils, and basophils; monocytes/macrophages/dendritic cells (MPs), erythrocytes (EPs), and megakaryocytes (MkPs) . Each step of the hematopoietic progression—survival, proliferation, or differentiation—is well-supported by cytokines and growth factors. Both hematopoietic cell development and cytokines are often arranged in a hierarchical system with broadly acting cytokine groups such as stem cell factor (SCF), Tpo, (interleukin-7) (IL-7); IL-3 (interleukin-3 (IL-3), IL-7, SCF, Tpo, granulocyte-macrophage colony-stimulating factor (GMCSF); Tpo, Epo, interleukin-2 (IL-2), IL-3, interleukin-4 (IL-4), interleukin-5 (IL-5), IL-7, granulocyte colony stimulating factor (GCSF), macrophage colony-stimulating factor (M-CSF), SCF; act during differentiation of specific lineages like primitive progenitor cells, committed precursor cells and lineage-committed cells, respectively . During the initial stages of hematopoietic cell development, IL-7 initiates CLP formation, whereas SCF, Tpo and SCF regulate CMP proliferation from HSC. The CMP differentiates into MEPs (IL-3SCF and Tpo) and GMs (GMCSF). Later, the megakaryocytic and erythroid progenitors are primarily regulated by Tpo (MEP-Megakaryocytes-Platelets) and Epo (MEPs-EPs-Erythrocytes). In addition to its activity as a regulator of the megakaryocytic lineage, Tpo also has non-redundant activity on stem cells. In contrast, Epo primarily regulates levels of erythrocyte progenitors and has pleiotropic effects both within the hematopoietic system and in other tissues . It is apparent that apart from Tpo and Epo, more lineage-restricted cytokines like M-CSF (GMs-MPs-macrophage/monocyte/dendritic cells) and GMCSF [GMs-GPs-granulocytes (neutrophil/basophil/eosinophil)] regulate the respective monocytic and granulocytic lineages—GCSF, IL-5, SCF, and IL-3IL-5 in the case of eosinophils, SCF for basophils or mast cells, and GCSF for neutrophils . Likewise, IL-7 acting on the multipotential cells regulates the differentiation of CLPs into TNKs and BCPs, initiating the lymphocytic lineage development processes. The TNKs then differentiate into TCPs (IL-2 and IL-7) and NKPs (IL-7), whereas IL-4 is crucial for differentiation of BCPs into B-cells. These lineage-committed cells like TCPs give rise to T-cells (IL-7 and IL-2) and NKPs differentiate as NK cells (IL-5) . In addition to their controlling role in survival, proliferation, and maturation of hematopoietic lineages, some (but not all) cytokines/cytokine receptors transduce a genuine lineage-determining signal at some points in hematopoiesis, especially at the point of divergence of the myeloid and lymphoid lineages. Deletions of Class I cytokine receptors block the instructive signaling by cytokines and results in severe combined immunodeficiency (IL-2 and IL-7 deletions); eosinopenia, alveolar proteinosis (IL-5, IL-3 GMCSFletions); embryonic lethal, cardiac (ventricular) hypoplasia, failure of definitive erythropoiesis, partial defect yolk sac erythropoiesis (deletions in Epo gene); Thrombocytopenia (c-Mpl/Tpo receptor deletions leading to deficiency in Tpo regulation); chronic neutropenia, impaired neutrophil mobility (absence of GMCSF); etc., to mention a few . Such cytokines that stimulate hematopoiesis is part of routine care in subjects with anemia, neutropenia, thrombocytopenia, or all these conditions as a result of natural or iatrogenic causes . Moreover, as multiple signaling pathways (e.g., Notch, Sonic hedgehog apart from WNT) and transcription factors [e.g., Homeobox-B4 (HOXB4)] are emerging as regulators of HSC self-renewal, it may be important to determine if and how these signals are integrated to regulate HSC development. Answering these questions will enable us to understand the signals that regulate HSCs specifically and stem cell growth in general. In the long term, this knowledge may lead to the ability to create methods to maintain the undifferentiated state of hematopoietic stem cells in culture and have numerous practical ramifications for transplantation and regenerative therapies .
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