Hematopoiesis

Abstract

Enormous numbers of adult blood cells are constantly regenerated throughout life from hematopoietic stem cells through a series of progenitor stages. Accessibility, robust functional assays, well-established prospective isolation, and successful clinical application made hematopoiesis the classical mammalian stem cell system. Most of the basic concepts of stem cell biology have been defined in this system. At the same time, many long-standing disputes in hematopoiesis research illustrate our still limited understanding. Here we discuss the embryonic development and lifelong maintenance of the hematopoietic system, its cellular components, and some of the hypotheses about the molecular mechanisms involved in controlling hematopoietic cell fates.

Figure 1.

Embryonic hematopoietic development. Anatomical sites and timing of hematopoietic cell generation, maintenance, and expansion during embryonic development. Hematopoietic cells are generated de novo in both extra- (yolk sac, allantois, placenta) and intraembryonic (AGM region) tissues. Cells are migrating to other sites for expansion and ultimately long-term maintenance throughout adult life. dpc, days after conception; wpc, weeks after conception.

Figure 2.

Adult hematopoietic differentiation hierarchy. Long-term self-renewing HSCs are at the apex of a hierarchy of multiple progenitor cell stages giving rise to all blood cell lineages. Distinct HSPC stages have been described by correlating surface marker expression and functional properties for prospective isolation, both in the murine and human systems. Murine hematopoiesis is currently defined in more detail and therefore displayed here. Corresponding human HSPC populations with their markers are indicated. HSCs differentiate into all blood cell lineages via long described (bold arrows) and potentially also or alternatively more recently described differentiation routes (thin arrows). It is important to point out that this model is only a simplified representation of current knowledge and will continue to change. Individual murine HSCs show an intrinsic lineage-biased repopulating ability, generating either more myeloid or lymphoid cells or a balanced mixture. These HSC subgroups can be enriched by detecting various levels of CD150 expression or Hoechst efflux. HSC, hematopoietic stem cell; MPP, multipotent progenitor; LT-, long-term repopulating; IT-, intermediate-term repopulating; ST-, short-term repopulating; LMPP, lymphoid-primed MPP; ELP, early lymphoid progenitor; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; GMP, granulocyte–macrophage progenitor; MEP, megakaryocyte–erythrocyte progenitor; CDP, common dendritic progenitor; MDP, monocyte–dendritic cell progenitor; NK, natural killer cell.

Figure 3.

Continuous single-cell observations are required for a comprehensive understanding of dynamic cellular behavior. (A) Individual cell-fate decisions are the reason for the behavior of the complete hematopoietic system in health and disease, and must therefore be quantified. They are influenced by factors like cytokines, extracellular matrix (ECM), or membrane-bound signaling molecules in many different niches. (B) Only continuous single-cell observation allows unambiguous conclusions about cell-fate choices in complex cell systems. Discontinuous input/output analyses—even when done at the single-cell level—cannot distinguish between different combinations of cell-fate decisions leading to the same output of a cellular system, and therefore lead to ambiguous conclusions.

Figure 4.

Network motifs for induction and maintenance of lineage commitment. Simplified examples of molecular mechanisms and networks of stable commitment induction and propagation in erythroid (A), B-lymphoid (B), T-lymphoid (C), and myeloid (D) cells. Direct or indirect activation (arrows) and repression (barred lines) of individual factor expression are indicated. Transcription factors are depicted in white, surface receptors in gray. Dashed lines represent indirect interactions.

Figure 5.

Possible influence of extracellular signals on production of lineage-committed cells. Extrinsic signals by, for example, hematopoietic cytokines may instruct the lineage choice of multipotent cells. Alternatively, extrinsic signals could merely enable survival, proliferation, and maturation signals of cells that have already committed to one lineage independently of the extrinsic signal. Importantly, static analyses at the start and end of an experiment would lead to identical data in both situations, and continuous single-cell observations are required for definitive conclusions about cytokine function.