Pluripotent Stem Cells and Hematopoiesis
Pluripotent stem cells (PSCs) can self-renew and differentiate into any cell type, including blood cells. In hematopoiesis, PSCs first become mesoderm, then hematopoietic progenitor cells, which give rise to all blood lineages. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are key in modeling and treating blood disorders, offering potential for gene editing and personalized therapies.
Pathway Summary
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.
Pluripotent Stem Cells and Hematopoiesis Genes list
Explore Genes related to Pluripotent Stem Cells and Hematopoiesis
- CD4 moleculeCD4
icon_0171_ls_qf_save_program-s - 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 - C-X-C motif chemokine ligand 8CXCL8
icon_0171_ls_qf_save_program-s - erythropoietinEPO
icon_0171_ls_qf_save_program-s - interleukin 10IL10
icon_0171_ls_qf_save_program-s - interleukin 11IL11
icon_0171_ls_qf_save_program-s - interleukin 1 alphaIL1A
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 6IL6
icon_0171_ls_qf_save_program-s - interleukin 7IL7
icon_0171_ls_qf_save_program-s - interleukin 9IL9
icon_0171_ls_qf_save_program-s - KIT ligandKITLG
icon_0171_ls_qf_save_program-s - LIF interleukin 6 family cytokineLIF
icon_0171_ls_qf_save_program-s
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What are pluripotent stem cells?
Pluripotent stem cells are cells that are not lineage restricted – they have the ability to self-renew and to become any cell type within the body. This includes the ability to become blood cells, which arise from the mesoderm lineage, but also includes the ability to become very different cell types arising from ectoderm (for example, neural cells) and endoderm lineages (for example, cells lining the digestive and respiratory systems). This is in contrast to hematopoietic stem cells, which can differentiate into all different blood cell types but are fully committed to the hematopoietic lineage. The developmental plasticity of PSCs makes them uniquely suited for regenerative medicine and in vitro modeling of early hematopoietic events.
The origin and potential of pluripotent stem cells involved in hematopoiesis have a significant influence on the pathways that drive the process of blood cell formation and its outcomes.
Source of pluripotent stem cells
Since pluripotent stem cells serve as the foundational source for generating all blood cell types during hematopoiesis, understanding their origin is essential for studying how these cells contribute to hematopoietic lineages in both research and therapeutic contexts.
There are two primary sources of pluripotent stem cells:
- Embryonic stem cells (ESCs) are derived from the inner cell mass of the blastocyst during early embryogenesis and give rise to all somatic and germline tissues through normal development.
- Induced pluripotent stem cells (iPSCs) are created in vitro by reprogramming differentiated somatic cells, typically through the forced expression of transcription factors such as OCT4, SOX2, KLF4 and c-MYC. This reprogramming returns cells to a pluripotent state, enabling them to differentiate into any cell type, including hematopoietic lineages.
Difference between totipotent and pluripotent stem cells
Totipotent stem cells have the ability to form all types of cells, including cells like the placenta that support embryonic development but are not part of the embryo. Pluripotent stem cells have the ability to form all types of cells except for those that support embryonic development.
How do pluripotent stem cells differentiate into blood cells?
Hematopoiesis from pluripotent stem cells is a stepwise process that begins with the induction of PSCs to become mesoderm (1). Mesoderm then further differentiates to give rise to multiple lineages, including the hematopoietic lineage descended from hematopoietic progenitor cells (HPCs). Although they have limited ability to self-renew, the HPCs give rise to all myeloid and lymphoid lineages through further differentiation.
Transcription factors including RUNX1, GATA2 and TAL1 are essential for hematopoietic specification, while cytokines such as stem cell factor (SCF), interleukin-3 (IL-3), interleukin-6 (IL-6), erythropoietin (EPO) and thrombopoietin (TPO) direct lineage maturation in vitro.
Pluripotent stem cells in hematopoiesis research
In the laboratory, PSCs can be coaxed into hematopoietic lineages through stepwise differentiation protocols that recreate embryonic developmental cues. Co-culture with stromal cell lines such as OP9 can promote myeloid and lymphoid development, while defined cytokine cocktails can drive specific lineage outcomes.
PSCs in regenerative medicine and disease modeling
Patient-specific iPSCs offer a powerful platform for disease modeling, enabling researchers to recreate inherited blood disorders in vitro and test targeted therapies. For example, iPSCs from patients with sickle cell disease or β-thalassemia have been genetically corrected using CRISPR-Cas9 and differentiated into healthy red blood cells. PSC-derived immune effector cells, such as NK cells and T cells, are also being engineered with chimeric antigen receptors (CARs) to enhance anti-tumor activity (2).
References
- Slukvin I. Hematopoietic specification from human pluripotent stem cells: current advances and challenges toward de novo generation of hematopoietic stem cells. Blood. 2013;122(25):4035–4046.
- Li Y, Hermanson DL, Moriarity BS, Kaufman DS. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell. 2018 Aug 2;23(2):181–192.e5.