Haemopoietic Stem And Progenitor Cells
Haemopoiesis starts with a pluripotential stem cell that can by asymmetric cell division self‐renew but also give rise to the separate cell lineages. These cells are able to repopulate a bone marrow from which all stem cells have been eliminated by lethal irradiation or chemotherapy. This haemopoietic stem cell (HSC) is rare, perhaps 1 in every 20 million nucleated cells in bone marrow. Many of the cells are dormant and in mice it has been estimated that they enter cell cycle approximately every 20 weeks. Although its exact phenotype is unknown, on immunological testing the HSC is CD34+ CD38− and negative for lineage markers (Lin−) and has the appearance of a small or medium‐sized lymphocyte (see Fig. 23.3). The cells reside in specialized osteoblastic or vascular ‘niches’.
Cell differentiation occurs from the stem cell via committed haemopoietic progenitors which are restricted in their developmental potential (Fig. 1.2). The existence of the separate progenitor cells can be demonstrated by in vitro culture techniques. Very early progenitors are assayed by culture on bone marrow stroma as long‐term culture initiating cells, whereas late progenitors are generally assayed in semi‐solid media. An example is the earliest detectable mixed myeloid precursor which gives rise to granulocytes, erythrocytes, monocytes and megakaryocytes and is termed CFU (colony‐forming unit)‐ GEMM (Fig. 1.2). The bone marrow is also the primary site of origin of lymphocytes, which differentiate from a common lymphoid precursor. The spleen, lymph nodes and thymus are secondary sites of lymphocyte production (see Chapter 9).
The stem cell has the capability for self‐renewal (Fig. 1.3) so that marrow cellularity remains constant in a normal healthy steady state. There is considerable amplification in the system: one stem cell is capable of producing about 106 mature blood cells after 20 cell divisions (Fig. 1.3). In humans HSCs are capable of about 50 cell divisions, telomere shortening affecting viability. Under normal conditions most are dormant. With aging, the number of stem cells falls and the relative proportion giving rise to lymphoid rather than myeloid progenitors also falls. Stem cells also accumulate genetic mutations with age, an average of 8 at age 60, and these, either passenger or driver, may be present in tumours arising from these stem cells (see Chapter 11). The precursor cells are capable of responding to haemopoietic growth factors with increased production of one or other cell line when the need arises. The development of the mature cells (red cells, granulocytes, monocytes, megakaryocytes and lymphocytes) is considered further in other sections of this book.