Pathophysiology

STEM CELL FAILURE IN AA Direct and indirect stem cell injury

Iatrogenic bone marrow failure induced by chemo-therapeutic drugs or radiation is perhaps the best example of a direct injury to hematopoietic stem cells. While stem cells, due to their dormant nature, may be more resistant to certain cytotoxic drugs, clearly a dose-response relationship with the degree of stem cell damage can be established. Noniatrogenic direct stem cell injury is less well characterized. If a putative inciting agent directly destroys stem cells, causing a permanent depletion, the clinical presentation of cytope-nia may be delayed, precluding recognition of the causative agent. Regardless of the mechanism, direct stem cell damage is most likely random and can become obvious when certain critically low stem cell numbers are reached. None of these viral agents has been directly implicated in the pathogenesis of idio-pathic AA. In the case of drugs and chemical agents most notoriously implicated in the pathogenesis of AA, the direct toxicity as a mechanism of injury is also in question. However, the most compelling evidence exists that the mechanisms of stem cell damage in AA are indirectly mediated by the cells of the immune system (see below).8-10

Quantitative defect

Theoretically, failed blood cell production in AA could be attributed to a defect restricted to the progenitor cell compartment and/or involve a stem cell. Low numbers of hematopoietic progenitors, as measured by colony assays or by flow cytometry, have been a consistent finding in AA.11 16 Both the more committed as well as the immature (CD34+c-kir or CD34+CD38) progenitor cells are depleted.15 Hematopoietic progenitor cells from AA show decreased sensitivity to trophic signals,13 and colony formation by AA bone marrow cells remains unresponsive in vitro and in vivo, even to high levels of circulating hematopoietic growth factors present in most patients.17-19 Unlike in murine models, measurement of more immature progenitor and stem cells is not easily accomplished in humans.

The hematopoietic recovery following successful immunosuppression demonstrates that some stem cells must be spared from the pathologic process. Serial studies were conducted to determine the numbers of stem cells during the course of disease; a profound defect in the numbers may persist for a long time upon hematopoietic recovery, e.g., following successful immunosuppression.20,21 In most patients, a residual numeric defect may be permanent despite a full recovery of the blood counts. Complete reconstitution of the numbers may be found only in a minority of patients who sustained a complete remission.20 Nevertheless, serial studies suggested that at least partial recovery of stem cells is possible, and a highly depleted stem cell pool can sustain seemingly normal blood cell counts (Figure 41.1).

Qualitative defect

In multiple studies stromal function has been found to be unaffected in AA.22-24 The defect of the stem cells, rather than that of supporting stroma, has been elegantly demonstrated in experiments in which CD34+ cells from AA patients showed poor growth on allogeneic normal stromal layers, while normal CD34+ cells planted on the stroma derived from AA patients showed normal growth properties.1922 Clinically, stem cell transplantation is a highly successful therapy in AA, but stromal elements remain of host origin following transplantation.25 Damage to the stem cell compartment in acquired AA is likely the main cause for the quantitative defect by all measures used to quantitate early hematopoietic cells. The number of colony-forming cells or long-term culture-initiating cells (LTC-IC) assayed from purified CD34+ population derived from AA patients is lower than that observed with normal CD34+ cells.12'2126 A decreased proportion of cycling cells has also been described in AA,11 suggesting that a blockade in cell cycling may precede apoptosis.27 28 Alternatively, quiescent cells are resistant to apoptotic stimuli, and cycling cells may be selectively inhibited or killed, effectively turning off all active stem cells.

Apoptosis, telomere shortening, and genetic damage

In AA, an abundance of trophic signals and a relative lack of efficacy of hematopoietic growth factors argue against their deficiency as a mechanism of apoptosis.17 However, an increased apoptotic fraction within CD34+

Figure 41.1 Fate of hematopoietic stem cell compartment in aplastic anemia. Under normal circumstances, within the stem cell compartment, a certain number of cycling stem cells maintain supplies of committed progenitor cells that produce mature blood cells. In immune-mediated aplastic anemia, all stages of hematopoietic development are affected but the decrease of the stem cell numbers is the essential lesion, explaining involvement of all blood cell lineages. After successful treatment (e.g., with immunosuppression), removal of inhibitory stimuli may allow the remaining stem cells to compensate their numeric deficiency with increased production of committed progenitor cells, and, as a result, normal or seminormal blood cell counts can be maintained (right portion). However, a limited regeneration of stem cells may be possible (either within the compartment itself or through recruitment from the more pluripotent pool) and the normal blood cell production is restored (left)

Modes of recovery

Figure 41.1 Fate of hematopoietic stem cell compartment in aplastic anemia. Under normal circumstances, within the stem cell compartment, a certain number of cycling stem cells maintain supplies of committed progenitor cells that produce mature blood cells. In immune-mediated aplastic anemia, all stages of hematopoietic development are affected but the decrease of the stem cell numbers is the essential lesion, explaining involvement of all blood cell lineages. After successful treatment (e.g., with immunosuppression), removal of inhibitory stimuli may allow the remaining stem cells to compensate their numeric deficiency with increased production of committed progenitor cells, and, as a result, normal or seminormal blood cell counts can be maintained (right portion). However, a limited regeneration of stem cells may be possible (either within the compartment itself or through recruitment from the more pluripotent pool) and the normal blood cell production is restored (left)

cell populations derived from AA has been demonstrated.29-31 In addition to proapoptotic cytokines and growth factors withdrawal, apoptosis in AA may be mediated by nitric oxide or oxygen radicals secreted by CD34+ cells in paracrine fashion.3233

Frequent evolution of clonal disease3435 suggests that the process leading to the depletion of stem cells may promote acquisition of stem cell damage, and the expansion of the dysplastic clone may be the result of a clonal escape, possibly due to a different susceptibility to depletion mechanisms between normal and mutated stem cells. It is also possible that the depletion of normal stem cells may more likely facilitate the recruitment of a preexisting defective (under normal circumstances quiescent) stem cell (known as the oligoclonality theory). Alternatively, some of the proposed proapoptotic signals may serve as potential DNA-damaging agents. The putative mechanisms may involve generation of reactive oxygen and nitrogen species capable of damaging the DNA.

In true stem cells, self-renewal does not result in telomere shortening, but upon recruitment and commitment the telomere length progressively declines with each division.36-38 In general, shorter telomeres, measured by various methods, were reported in AA.38-40 While patients with chronic moderate AA showed short telomeres, in acute severe cytopenia, shortening of the telomeres may not be evident due to the blocking of stem cell cycling. Upon recovery, due to the recruitment of new stem cells, telomeres of the progeny may provide longer measurements again, or, if the stem cell number operating at a given time is small (and normal cell counts maintained), telomere shortening may be more pronounced. In general, once a critical telomere length is reached, chromosomes may become unstable. Such a mechanism could explain the evolution of clonal karyotypic defects in AA, but shortened chromosomes were not consistently found in AA patients who evolved into myelodysplasia.

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