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Hematopoiesis

Hematopoiesis, the formation of new blood cells, relies on critical signaling pathways such as Wnt, Notch, Hedgehog, fibroblast growth factor (FGF), Hippo and transforming growth factor-β (TGFβ). These pathways are essential not only for normal blood cell development but also play significant roles in hematopoietic disorders and cancers.

Hematopoiesis Overview

Hematopoiesis is the production of blood cells, including white blood cells, red blood cells and platelets, which starts during embryonic development and continues throughout life to ensure a constant supply of blood and immune system cells. This lifelong process supports essential bodily functions, including fighting pathogens, blood clotting and tissue repair.

Hematopoiesis occurs in the yolk sac, aorta-gonad-mesonephros, spleen and liver during embryonic and fetal development and in the bone marrow and lymph nodes during adulthood. The process depends on hematopoietic stem cells (HSCs). These HSCs may self-renew or divide into progenitor cells. These progenitor cells then divide and differentiate into specialized cells until they become white blood cells, red blood cells, or platelets (1).

Stem Cells in Hematopoiesis

Hematopoietic stem cells (HSCs) are pluripotent primitive cells present in different organs, including peripheral blood, bone marrow and umbilical cord blood (2). These cells can create a complete hematopoietic system with their ability to self-renew or divide into progenitor cells. These progenitor cells then further develop into white blood cells, red blood cells, or platelets. HSCs can be grouped into long-term HSCs, short-term HSCs and multipotent progenitors based on how long they can repopulate (3).

Key Signaling Pathways in Hematopoiesis

Hematopoiesis is strictly regulated by cytokines, growth factors, transcription factors and other molecules primarily released in the bone marrow microenvironment. Wnt, Notch, Hedgehog, TGFβ and other signaling pathways are crucial in blood cell formation. Their abnormal activation contributes to the development and progression of blood disorders and cancer (4).

FLT3 Signaling

FLT3 is a cytokine receptor belonging to the class III receptor tyrosine kinase group. It is expressed by myeloid, lymphoid and dendritic cells and plays a crucial role in the growth and differentiation of hematopoietic lineages. Its signaling is activated with the binding of cytokine FL to FLT3 (5).

Mutations of FLT3 are implicated in the development and progression of blood cancers such as acute myeloid leukemia (AML) and myelodysplastic syndrome. Patients with  FLT3 mutations also tend to have a poor clinical prognosis (5).

IL-3 Signaling

Interleukin-3 (IL-3), a monomeric glycoprotein, is a growth and differentiation factor of the hematopoietic bone marrow cell. It is produced by lymphoid cells, mast cells and eosinophils. Well recognized for regulating hematopoiesis, IL-3 stimulates the proliferation and maintenance of hematopoietic stem and progenitor cells (6, 7).

Aberrant IL-3 signaling contributes to the progression and survival of hematologic malignancies. Its role is particularly significant in acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm. Studies have found that CD123, the α chain of the IL-3 receptor, is overexpressed in these conditions and associated with lower survival in patients with acute myeloid leukemia (8). IL-3 has also been found to be significantly higher in patients with multiple myeloma compared to healthy controls (9).

IL-3 and its receptors are potential therapeutic targets for hematologic malignancies.

Lymphotoxin β Receptor Signaling

Lymphotoxin β Receptor (LTβR) is a tumor necrosis factor receptor expressed by epithelial cells, stromal cells, dendritic cells and macrophages. Signaling occurs when this receptor interacts with its ligands membrane heterotrimeric lymphotoxin LTα1β2 and homotrimeric LIGHT (10).

LTβR signaling influences hematopoiesis by regulating quiescence and self-renewal of HSCs and has been implicated in the development and progression of hematological cancers. For example, leukemia relies on aberrant LTβR signaling for the self-renewal and differentiation of leukemic stem cells (LSCs) (11).

Researchers are working on therapeutic strategies that inhibit or promote LTβR signaling to develop better treatments for blood cancers.

Wnt Signaling

The Wnt family comprises 19 Wnt genes, which are extracellularly secreted glycoproteins that act as growth factors, and ten receptors. Many Wnt genes, including Wnt2b, Wnt3a, Wnt5a and Wnt10b, are expressed in the bone marrow (12).

The Wnt pathway, which may be β-catenin-dependent or β-catenin-independent, is essential for regulating developmental hematopoiesis from embryonic stages throughout life. In particular, it has been shown to regulate HSC fate, renewal, differentiation and maintenance. For instance,  Wnt5a and Wnt5b work through β-catenin-independent signaling to support hematopoiesis, bone marrow growth and the final stages of hematopoietic stem cell development. In addition, they stimulate progenitor cell growth, support myeloid development and maintain inactive, long-term HSCs to prevent HSC exhaustion. Wnt3a contributes to hematopoietic cell proliferation and short-term HSC cell cycle entry in adults and regulates lymphoid development (13).

Dysregulated Wnt signaling is associated with blood cancers like leukemia, lymphomas and multiple myeloma. Hence, targeting this pathway may improve treatments for these diseases (14).

Notch Signaling

Notch is an evolutionarily conserved signaling pathway involving Notch receptors (Notch1-4), Delta-like ligands (Dll)-1,-3 and -4 and Serrate-like ligands (Jagged-1 and -2). This pathway is activated when a ligand expressed by one cell binds to a Notch receptor expressed on an adjacent cell (15).

Notch is thought to play a central role in regulating the development of definitive HSCs, which are cells that are responsible for forming mature blood and immune cells. For instance, Notch1 is necessary for producing HSCs in embryogenesis, while Notch2 supports HSC regeneration after bone marrow suppression (16).

Numerous animal studies have demonstrated Notch signaling’s role in regulating HSC emergence, development, differentiation, self-renewal and maintenance and the pathogenesis of hematopoietic diseases. A deeper understanding of the role of Notch signaling in hematopoiesis may be promising for developing improved therapeutic strategies for hematopoietic disorders (15, 17, 18).

Hedgehog Signaling

The Hedgehog signaling pathway is a highly conserved signaling pathway regulating embryo hematopoiesis and other developmental processes. It is initiated when Sonic Hedgehog (SHH), Indian Hedgehog (IHH), or Desert Hedgehog (DHH) binds to patched (PTCH), a 12-transmembrane receptor (19). It is vital for biological processes such as cell proliferation, differentiation and maintenance, embryonic organogenesis, metabolic control, inflammation, stem cell maintenance and tissue repair (20).

In particular, Hedgehog signaling enables the initiation of hematopoiesis during gastrulation. Animal studies show that IHH released from the visceral endoderm during embryogenesis enables the production of hemogenic and vasculogenic mesodermal cells by inducing the expression of Hedgehog components, including PTCH1, SMO and GLI1. When IHH or SMO is inhibited or deleted, these mesodermal cells cannot create the yolk sac blood islands necessary for early embryonic erythropoiesis and vascularization (21).

In definitive hematopoiesis, activated Hedgehog signaling contributes to increased HSC formation in preclinical studies. On the other hand, loss of pathway signaling due to GLI1 mutation results in reduced long-term HSC proliferation.

More research on how Hedgehog signaling contributes to hematopoiesis may improve current treatment strategies for diseases, including acute myeloid leukemia and myelodysplastic syndrome (22).

FGF, Hippo and TGFβ are other pathways that regulate the different stages of hematopoiesis to, for instance, prevent HSC decline or excessive HSC formation. Disruption of these regulatory pathways may result in blood disorders, such as leukemia. These pathways may also be relevant for creating better and targeted treatment (23).

References

  1. StatPearls [Internet] https://www.ncbi.nlm.nih.gov/books/NBK534246/# (Accessed June 24, 2024)
  2. Lee JY, Hong SH. Hematopoietic Stem Cells and Their Roles in Tissue Regeneration. Int J Stem Cells. 2020;13(1):1-12. doi:10.15283/ijsc19127
  3. Ng AP, Alexander WS. Haematopoietic stem cells: past, present and future. Cell Death Discov. 2017;3:17002. Published 2017 Feb 6.
  4. Cenariu D, Iluta S, Zimta AA, et al. Extramedullary Hematopoiesis of the Liver and Spleen. J Clin Med. 2021;10(24):5831. Published 2021 Dec 13.
  5. Tsapogas P, Mooney CJ, Brown G, Rolink A. The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis. Int J Mol Sci. 2017;18(6):1115. Published 2017 May 24.
  6. ScienceDirect https://www.sciencedirect.com/topics/medicine-and-dentistry/interleukin-3 (Accessed June 24, 2024)
  7. Tajer P, Canté-Barrett K, Naber BAE, et al. IL3 Has a Detrimental Effect on Hematopoietic Stem Cell Self-Renewal in Transplantation Settings. Int J Mol Sci. 2022;23(21):12736. Published 2022 Oct 22.
  8. Borriello F, Galdiero MR, Varricchi G, Loffredo S, Spadaro G, Marone G. Innate Immune Modulation by GM-CSF and IL-3 in Health and Disease. Int J Mol Sci. 2019;20(4):834. Published 2019 Feb 15.
  9. ScienceDirect https://www.sciencedirect.com/topics/neuroscience/interleukin-3 (Accessed June 24, 2024)
  10. Shou Y, Koroleva E, Spencer CM, et al. Redefining the Role of Lymphotoxin Beta Receptor in the Maintenance of Lymphoid Organs and Immune Cell Homeostasis in Adulthood. Front Immunol. 2021;12:712632. Published 2021 Jul 15.
  11. Höpner SS, Raykova A, Radpour R, et al. LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells. Nat Commun. 2021;12(1):1065. Published 2021 Feb 16.
  12. Nemeth MJ, Bodine DM. Regulation of hematopoiesis and the hematopoietic stem cell niche by Wnt signaling pathways. Cell Res. 2007;17(9):746-758.
  13. Mastelaro de Rezende M, Zenker Justo G, Julian Paredes-Gamero E, Gosens R. Wnt-5A/B Signaling in Hematopoiesis throughout Life. Cells. 2020;9(8):1801. Published 2020 Jul 29.
  14. Staal FJ, Clevers HC. WNT signalling and haematopoiesis: a WNT-WNT situation. Nat Rev Immunol. 2005;5(1):21-30.
  15. Ge Y, Wang J, Zhang H, Li J, Ye M, Jin X. Fate of hematopoietic stem cells determined by Notch1 signaling (Review). Exp Ther Med. 2022;23(2):170.
  16. Staal FJ, Chhatta A, Mikkers H. Caught in a Wnt storm: Complexities of Wnt signaling in hematopoiesis. Exp Hematol. 2016;44(6):451-457.
  17. Lampreia FP, Carmelo JG, Anjos-Afonso F. Notch Signaling in the Regulation of Hematopoietic Stem Cell. Curr Stem Cell Rep. 2017;3(3):202-209.
  18. Huang C, Yang D, Ye GW, Powell CA, Guo P. Vascular Notch Signaling in Stress Hematopoiesis. Front Cell Dev Biol. 2021;8:606448. Published 2021 Jan 21.
  19. Tibes R, Mesa RA. Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies. J Hematol Oncol. 2014;7:18. Published 2014 Mar 5.
  20. Chen J, Sun Y, Chi Z. Regulation of hematopoiesis by hedgehog signaling (Review). Mol Med Rep. 2023;27(5):100.
  21. Tesanovic S, Krenn PW, Aberger F. Hedgehog/GLI signaling in hematopoietic development and acute myeloid leukemia-From bench to bedside. Front Cell Dev Biol. 2022;10:944760. Published 2022 Aug 5.
  22. Lim Y, Matsui W. Hedgehog signaling in hematopoiesis. Crit Rev Eukaryot Gene Expr. 2010;20(2):129-139.
  23. Blank U, Karlsson S. TGF-β signaling in the control of hematopoietic stem cells. Blood. 2015;125(23):3542-3550.
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