40.6:
Lineage Commitment
Lineage commitment is an irreversible process where hematopoietic stem cells or HSCs lose their multipotency and differentiate into precursors of a particular cell type.
The stepwise process is primarily determined by growth factors called cytokines, which help the progenitors give rise to specific blood and immune cells.
First, the HSCs divide and form hematopoietic progenitor cells or HPCs. Based on the type of cytokine receptor present on HPCs, they differentiate into common myeloid progenitors or CMPs, or common lymphoid progenitors, or CLPs.
The primed progenitors follow the cytokine gradient and migrate to cytokine-enriched regions in the bone marrow, except for T cell progenitors, which migrate to the thymus.
CMPs further develop into megakaryocyte-erythroid progenitors or MEPs, and granulocyte-macrophage progenitors or GMPs, yielding erythrocytes, granulocytes and monocytes.
CLPs differentiate into precursors of natural killer cells, T-cells, or B cells.
40.6:
Lineage Commitment
Commitment is the process whereby stem cells:
- lose their ability to form all cell types and
- irreversibly change into a specific type.
The multipotent hematopoietic stem cells, (HSCs), differentiate into the multipotent hematopoietic progenitor cells, (HPCs). The HPCs express many lineage-specific cytokine receptors. Each of these receptors binds specific cytokines, activates distinct signaling pathways, and expresses a particular gene set. The HPCs further differentiate to form committed progenitors, forming either common myeloid progenitors (CMPs) or common lymphoid progenitors (CLPs). The CMPs and CLPs proliferate, self-renew, and further differentiate into mature blood cells and immune cells depending on the receptors they express and the specific cytokines that bind. For example:
- Thrombopoietin (TpoR)- They help progenitors differentiate into megakaryocytes or platelets.
- Erythropoietin (EpoR)-These receptors promote the development of erythrocytes.
- Macrophage-colony stimulating factor (M-CSFR)-These receptors regulate the formation of macrophages.
- Granulocyte-colony stimulating factor (G-CSFR)- They help HPCs differentiate into granulocytes.
- Interleukin-7 receptor (IL-7R)- They help progenitor cells become lymphocytes.
Thus, lineage commitment helps HSCs lose their multipotency and differentiate into more restricted cell fate.
Suggested Reading
- Xu, J., Du, Y., & Deng, H. (2015). Direct lineage reprogramming: strategies, mechanisms, and applications. Cell stem cell, 16(2), 119-134.
- Pouzolles, M., Oburoglu, L., Taylor, N., & Zimmermann, V. S. (2016). Hematopoietic stem cell lineage specification. Current Opinion in Hematology, 23(4), 311-317.
- Purohit, S. J., Stephan, R. P., Kim, H. G., Herrin, B. R., Gartland, L., & Klug, C. A. (2003). Determination of lymphoid cell fate is dependent on the expression status of the IL-7 receptor. The EMBO journal, 22(20), 5511-5521.
- Brown, G. (2020). Towards a new understanding of decision-making by hematopoietic stem cells. International Journal of Molecular Sciences, 21(7), 2362.
- Zhu, J., & Emerson, S. G. (2002). Hematopoietic cytokines, transcription factors, and lineage commitment. Oncogene, 21(21), 3295-3313.