Aging of the lymphohematopoietic system often manifests as a blunted response to hematopoietic stress and is thought to be associated with an increased incidence of neoplasia, autoimmune diseases, and infections in elderly people. Although the physiological basis of this suboptimal response remains unclear, our understanding of human hematopoiesis has increased exponentially over the last two decades. However, most of the initial breakthroughs, as well as the seminal findings in the biology of hematopoiesis, have occurred in murine models. This review will discuss (1) the biology of hematopoiesis, (2) age-related changes in lymphohematopoiesis, and (3) indications for the use of hematopoietic growth factors in elderly patients.
The hematopoietic system derives from a small pool of hematopoietic stem cells (HSCs), which can either self-renew or differentiate along one of several lineages to form mature leukocytes, erythrocytes, or platelets. HSCs differentiate into mature cells through an intermediate set of committed progenitors and precursors, each with decreasing self-renewal potential and increasing lineage commitment. Hematopoiesis is tightly regulated by a complex series of interactions between HSCs, their stromal microenvironment, and diffusible regulatory molecules (hematopoietic growth factors) that effect cellular proliferation. The orderly development of the hematopoietic system in vivo and the maintenance of homeostasis require that a strict balance be maintained between self-renewal, differentiation, maturation, and cell loss.
HSCs cannot be directly observed, but are defined and identified by their ability to reconstitute and maintain hematopoiesis. The earliest morphologically recognizable cells of the myeloid and erythroid series are the myeloblasts and proerythroblasts (Figure 101-1). These cells are derived from morphologically unrecognizable progenitors that were first identified by in vitro culture techniques. There are two forms of erythroid progenitors: a more primitive precursor referred to as a burst-forming unit–erythroid (BFU-E), and a more mature progenitor referred to as the colony-forming unit–erythroid (CFU-E). A committed myeloid progenitor, also known as colony-forming unit–granulocyte/macrophage (CFU-GM), is the immediate precursor of the myeloblast. The committed progenitor cell compartments are supplied, in turn, by a common pluripotent stem cell, which has the capacity to differentiate into either hematopoietic or lymphoid cells. Figure 101-1 shows the hierarchy of cellular proliferation and differentiation in this pathway. The pluripotent HSC is called a colony-forming unit–spleen (CFU-S) by virtue of its ability (1) to produce colonies in spleens of lethally irradiated mice and (2) to repopulate the marrow of lethally irradiated recipients. There is evidence that the number of CFU-S in cell cycle is minimal, but that cycling can be greatly increased if demands for regeneration are increased. The CFU-S has a heterogeneous self-renewal capacity whereby an uncommitted CFU-S with high self-renewal capacity produces more committed CFU-S with decreasing self-renewal capacity and increasing differentiation potential.
The hierarchy and production of hematoietic precursors from primitive pluripotent stem cells.
Modern multichannel flow cytometry together with the availability of antibodies ...