Martha Pritchett Mims - Handbook of Benign Hematology

Figure 1.2 Sites of hematopoiesis in different stages of life.

HSCs AND THE HEMATOPOIETIC HIERARCHY

The hematopoietic differentiation cascade is akin to an inverted tree, starting with a small pool of HSCs that develop into a larger pool of progenitors, which then further differentiate into many intermediates and finally develop into different mature blood cells. As the cells travel down their hierarchy, they lose the ability to differentiate into other cell lines and progressively become committed to one lineage, that is, lineage-committed progenitors.

HSCs choose early whether to self-renew or to differentiate into more mature cells, with two models proposed to describe this choice, the stochastic (supportive) and the instructive. In the stochastic model, the choice of self-renewal versus differentiation is random. In contrast, in the instructive model, certain microenvironment factors and cytokines directly influence this decision. Notably, cytokines have critical but different roles in both models. In the instructive model, cytokines actively influence the decision, while in the stochastic model, cytokines do not influence the decision but support the survival and proliferation of progenitor cells that eventually differentiate into mature cells (). This issue remains controversial with conflicting data supporting both models.

HSCs are further subclassified as long term (LT-HSCs) and short term (ST-HSCs). The main role of LT-HSCs is self-renewal, and most of their progeny will follow this pathway, while lesser numbers become ST-HSCs ().

Hematopoietic progenitors can be classified into multilineage progenitors and single-lineage progenitors according to their differentiation potential. As illustrated in ). The timing of appearance, the morphology, the cellular components, and the cytokine requirements of the colonies arising in these assays define each of the intermediate forms, with the convention that a cell population identified by a particular assay is referred to by the assay name. CLPs ultimately differentiate into B, T, and NK cells. While myeloid and lymphoid lineages are thought to arise independently, some studies have suggested that the granulocytemacrophage progenitor (GMP) can also be derived from LMP.

Whereas many of the intermediates are not morphologically distinguishable, the majority of the final differentiation steps toward individual lineages can be identified by conventional histochemistry, where a blast form gives rise to more mature forms that progressively resemble the fully differentiated elements. lists the different types of mature blood cells as well as their morphologic characteristics and function.

CLUSTERS OF DIFFERENTIATION

As HSCs and progenitors differentiate, they acquire distinct cell surface antigen markers, also known as CDs, while losing the antigens associated with more primitive cells. CDs can be used to identify stem cells and diverse types of progenitors, intermediates, and mature blood cells of different lineages, even at stages when morphology alone would not be enough for cell identification. Identifying cell subpopulations via CDs is often done through monoclonal antibodies and flow cytometry, with marker panels being readily available commercially. The number of described CDs continues to grow and has exceeded 370 to date. Utilization of CDs in the clinical arena has revolutionized the way we understand, diagnose, classify, and treat hematologic diseases, and is now the standard of care to be incorporated in their diagnostic workup.