Hematopoietic Stem Cells and Hematopoiesis
Hematopoietic stem cells (HSCs) are multipotent cells in the bone marrow that give rise to all blood cell types through hematopoiesis. They have the ability to self-renew or to differentiate into progenitors of specific cell types, guided by cytokines like IL-7 and GM-CSF. This lifelong process ensures a steady blood cell supply but can also be augmented under duress. Mutations in HSCs can lead to clonal hematopoiesis, increasing risk for blood cancers and heart disease.
Pathway Summary
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.
Hematopoietic Stem Cells and Hematopoiesis Genes list
Explore Genes related to Hematopoietic Stem Cells and Hematopoiesis
- colony stimulating factor 1CSF1
icon_0171_ls_qf_save_program-s - colony stimulating factor 2CSF2
icon_0171_ls_qf_save_program-s - colony stimulating factor 3CSF3
icon_0171_ls_qf_save_program-s - erythropoietinEPO
icon_0171_ls_qf_save_program-s - interleukin 15IL15
icon_0171_ls_qf_save_program-s - interleukin 2IL2
icon_0171_ls_qf_save_program-s - interleukin 3IL3
icon_0171_ls_qf_save_program-s - interleukin 4IL4
icon_0171_ls_qf_save_program-s - interleukin 5IL5
icon_0171_ls_qf_save_program-s - interleukin 7IL7
icon_0171_ls_qf_save_program-s - KIT ligandKITLG
icon_0171_ls_qf_save_program-s - thrombopoietinTHPO
icon_0171_ls_qf_save_program-s
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What are hematopoietic stem cells?
Hematopoietic stem cells (HSCs), also known as blood stem cells, are multipotent adult stem cells found primarily in the bone marrow that, through the process of hematopoiesis, give rise to all blood cell types. While hematopoietic stem cells can differentiate into a multitude of blood cell types, they are committed to the hematopoietic lineage and have lost the ability to differentiate into other types of non-hematopoietic cells. This is in contrast to pluripotent stem cells, which retain the ability to differentiate into both hematopoietic and non-hematopoietic cells.
Hematopoietic stem cells occur in specialized bone marrow niches, which are microenvironments that regulate their quiescence, proliferation and differentiation through direct cell-cell contact and soluble signaling molecules. The origin and potential of hematopoietic stem cells involved in hematopoiesis have a significant influence on the pathways that drive the process of blood cell formation and its outcomes.
Self-renewal of hematopoietic stem cells
Hematopoietic stem cells have the ability to self-renew, forming two identical daughter cells that retain all of the characteristics of the parent cell – including its multipotency and ability to respond appropriately to environmental cues relevant to hematopoiesis. Long-term HSCs (LT-HSCs) sustain hematopoiesis for the lifetime of the organism, while short-term HSCs (ST-HSCs) contribute to blood production for weeks to months. Multipotent progenitors (MPPs) generated from HSCs have no self-renewal capacity but retain multilineage differentiation potential.
Is hematopoiesis from multipotent stem cells an ongoing process?
Hematopoietic stem cells are responsible for lifelong blood production. Given the short lifespan of mature blood cells, often measured in days to weeks, a basal state of hematopoiesis is maintained in order to provide a steady supply of new blood cells. Blood cell production can also be significantly increased in emergency situations such as infection, blood loss or systemic inflammation. This “emergency hematopoiesis” is mediated by inflammatory cytokines like IL-1 and TNF-α, which alter lineage output to meet immediate physiological demands.
Differentiation of hematopoietic stem cells
Hematopoiesis from multipotent stem cells is induced by cytokine signaling (1). Environmental cues determine the relevant cytokine, providing the instructions to push hematopoietic stem cells into becoming primitive progenitor cells. Either common lymphoid progenitor (CPL) cells arise in the case of IL-7, or common myeloid progenitor (CMP) cells in the case of GM-CSF and others.
These progenitor cells continue on to become committed precursor cells and finally lineage-committed cells based on the microenvironment, additional cytokine signals and downstream transcription factors regulated by those signals.
Transcription factors such as GATA-1, PU.1 and C/EBPα play key roles in locking in lineage fate, while epigenetic modifications fine-tune gene accessibility. The interplay between intrinsic transcriptional programs and extrinsic niche-derived cues ensures precise and adaptable blood cell production.
What is clonal hematopoiesis?
Clonal hematopoiesis (CH) occurs when a hematopoietic stem cell acquires a somatic mutation and passes it on to its progeny, leading to an expanded population of genetically identical blood cells. Over time, these clones become more prevalent, outnumbering non-mutated blood cells. Clonal hematopoiesis is more common in older adults and has been associated with blood cancers as well as cardiovascular disease.
Clonal hematopoiesis of indeterminate potential (CHIP) refers to a subset of clonal hematopoiesis where the mutation is associated with blood cancers, but the individual is not visibly affected (2). While CHIP is asymptomatic, it is linked to chronic inflammation, accelerated atherosclerosis and increased all-cause mortality, making it a significant focus of ongoing research.
Therapeutic applications of hematopoietic stem cells
Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy originally developed for treatment of hematologic malignancies, including leukemia. More recently, it has been adapted to provide treatment for severe immune-mediated disorders like multiple sclerosis. HSCT uses high-dose chemotherapy or radiation to eliminate compromised bone marrow cells, followed by infusion of hematopoietic stem cells to restore bone marrow function.
In autologous HSCT, a patient’s own stem cells are collected and reinfused. In contrast, allogeneic HSCT uses stem cells from a donor and offers the added benefit of a graft-versus-leukemia (GVL) effect, where donor immune cells help eliminate residual malignant cells. Allogeneic HSCT is commonly used in high-risk or relapsed leukemias due to this immunologic advantage, although it carries higher risks such as graft-versus-host disease (GVHD). Advances such as haploidentical transplants, improved conditioning regimens and better GVHD prophylaxis continue to expand HSCT’s safety and accessibility (3).
References
- Kandarakov O, Belyavsky A, Semenova E. Bone marrow niches of hematopoietic stem and progenitor cells. Int J Mol Sci. 2022;23(8):4462.
- Marnell CS, Bick A, Natarajan P. Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular diseases. J Mol Cell Cardiol. 2021;161:98-105.
- Balassa K, Danby R, Rocha V. Haematopoietic stem cell transplants: Principles and indications. Br J Hosp Med (Lond). 2019;80(1):33-39.