Aplastic Anemia: Pathophysiology and Treatment

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The cause of acquired AA was not clear for many years. While initially toxic effects were postulated as the reason of a quantitative HSC defect, nowadays autoimmune processes are considered mainly responsible for acquired AA occurring in the absence of a positive medical history of predisposing drugs, toxic agents or infections 1 — 4 Figure 1. In fact, while several pathomechanisms have been proposed, the greatest proportion of cases is likely due to uniform T-cell mediated auto-immunity and marrow destruction leading to defective, nearly absent hematopoiesis.

Clinical Hematology International

Furthermore, increases in T-helper 17 Th17 cells, the effector cells which produce the pro-inflammatory cytokine interleukin IL , were found in peripheral PB and BM of AA patients 1 , 3 , Indeed, especially Tregs from the BM of patients with AA were found to show pronounced quantitative as well as qualitative defects Figure 2.

Possible mechanisms contributing to bone marrow niche modulation and immune destruction of hematopoiesis in acquired aplastic anemia. Patients with acquired aplastic anemia AA display not only low numbers of hematopoietic stem cells HSC but also an altered hematopoietic niche. These events ultimately lead to reduced cell cycling and HSC cell death by apoptosis. Quantitative and qualitative deficits of regulatory T cells Tregs , which normally suppress auto-reactivity of other T cell populations, further stimulates T cell expansion. Regarding the stromal niche, impairments in osteoblastic, vascular, and perivascular HSC niches might contribute to defective hematopoiesis in patients with AA.

MSC aberrant alteration impair the maintaining of the immune homeostasis. Adipocytes AC are increased and pericytes are decreased PC and suppress hematopoiesis. Given the close interaction and regulatory feedback loops between resident hematopoietic and niche cells, it is not surprising that besides immune destruction, AA also associates with defects in non-hematopoietic BM microenvironment components. Further, BM lymphocytes from AA patients were shown to effectively inhibit hematopoietic cells from healthy donors in co-culture experiments In a very recent study by Sun et al.

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Macrophage depletion rescues thrombocytopenia, increases BM megakaryopoiesis, preserves platelet-primed stem cells, and increases the platelet-repopulating capacity of transplanted HSCs. Important components thereof are BM stromal cells, the extracellular matrix and local cytokine gradients 40 , The hematopoietic and non-hematopoietic elements of the BM closely interact with each other thereby sustaining and balancing hematopoiesis and hematopoietic output Figure 2. There is clear evidence that the BM microenvironment contains specialized HSC niches that include endothelial, perivascular and endosteal cells and provide key signals that regulate survival, quiescence, self-renewal and differentiation in HSCs 7.

Table 1. Selection of relevant studies about bone marrow microenvironment in aplastic anemia. Given the close interaction and regulatory feedback loops between resident hematopoietic and niche cells, it is not surprising that AA also associates with defects in non-hematopoietic BM microenvironment components.

As such, patients with AA showed markedly fewer endosteal cells, vascular cells, and perivascular cells compared with controls and loss of non-hematopoietic podoplanin-positive stromal cells was reported in a SAA mouse model In a further study, Chatterjee et al. They demonstrated that ROS reactive oxygen species generated in response to chemotherapy treatment indeed negatively impact the hematopoietic niche by deregulation of microenvironment related Notch-1 signaling and thereby alter the epigenetic status of the HSCs leading to devastating HSC damage.

They thus proposed that anti-oxidant based therapeutic strategies may be used to circumvent such adverse effects on hematopoiesis. Impairments in osteoblastic, vascular, and perivascular HSC niches might contribute to defective hematopoiesis in patients with AA 8 , Several studies have reported abnormal function and disordered components of the BM microenvironment in patients with AA and BMF 50 — For example, long-term cultures of BM stromal cells from patients with AA were shown to less robustly support hematopoiesis 44 , Mesenchymal stem cells MSCs are multipotent stromal cells that can differentiate into a variety of cell types: Namely adipocytes fat cells which give rise to marrow adipose tissue , chondrocytes cartilage cells , osteoblasts bone cells , and myocytes muscle cells 3.

Compared to healthy donors, MSCs derived from patients with AA showed aberrant morphology, decreased proliferation and clonogenic potential, increased apoptosis and a propensity to differentiate into adipogenic at the expense of osteogenic lineages 46 , 48 , 54 — 57 , even if significant heterogeneity among individual patient samples was observed.

Consistently, transcriptome analyses performed on these cells revealed altered expression especially of genes involved in cell proliferation, cell division, cell cycling, chemotaxis, hematopoietic cell interactions adipogenesis, and immune response in AA vs.

In contrast, more recent studies reported MSCs derived from patients with acquired AA to not differ from those collected from healthy controls 47 , In latter, stromal and other non-hematopoietic microenvironmental cells carry also themselves the congenital genetic lesion and might be thus affected by it. These data were further confirmed in a subsequent study from Cagnan et al. When compared to healthy donor derived MSCs, these SDS-MSCs especially displayed a marked decrease in vascular endothelial growth factor VEGF expression and defective ability to form correct vascular networks, capillary tubes and vessels In fact, using a genetic model of pre-leukemic SDS Zambetti et al.

It remains to be determined whether the enhanced risk of progression to malignant hematopoietic diseases which is much higher in Fanconi or SDS syndromes, when compared to acquired immune-mediated AA is in part also mediated by such qualitative changes in microenvironment cells. In a study by Bacigalupo et al. PB was examined as stem cell source in patients with AA.

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  6. Patients receiving BM had a significant survival advantage compared to patients receiving PB as stem cell source. Patients with PB as stem cell source had a higher incidence of acute and chronic graft-vs. This study reinforced that BM should be the preferred stem cell source for matched sibling transplants in acquired AA, irrespectively of the patients' age.

    A main reason for this recommendation is considered the increased risk of chronic GvHD after use of PB stem cells which should be especially avoided in patients transplanted for AA as a non-malignant disease. More recently, the survival advantage for BM grafts was confirmed across all age groups PB is an alternative stem cell source only in case of contraindications to a BM harvest, unwillingness of the donor to donate BM, or in case of second transplants after graft failure.

    Given the above mentioned quantitative MSC impairment in patients with acquired AA, it is tempting to speculate that BM transplantations may yield better results because they provide higher numbers of co-transplanted MSCs and supporting non-hematopoietic cell populations, which may promote niche reconstitution and thereby indirectly support nascent hematopoiesis in AA patients treated with allogeneic transplantations Figure 1. Indeed, as shown by De Felice et al. However, co-transplanted donor MSCs and non-hematopoietic populations contained in BM allo-transplants could perhaps transiently support the regeneration of the niche and therefore of the hematopoietic compartment in AA patients with quantitative niche defects.

    Alternatively, they might provide additional immune suppressive effects that improve the course of the disease 3.


    Wu et al. Regarding endosteal cells, no relevant changes could be found. Taken together, in patients with AA after allo-HCT vascular and perivascular niches are numerically restored, but the endosteal niche remains numerically quantitatively impaired. Of note, a systematic comparison between BM and PB allo-transplants was not yet performed, thus the role of co-transplanted non-hematopoietic BM cells for these effects remains elusive.

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    Postnatal vasculogenesis during physiological and pathological neovascularization occurs by endothelial progenitor cells with BM origin However, as shown by Wu et al. Cell-intrinsic and niche intrinsic variables influences the relationship of transplanted primitive hematopoietic cells to anatomical components of the trabecular niche In summary, AA is associated with reduced angiogenesis and reduced VEGF expression, which might contribute to disease pathogenesis.

    In a study by Deng et al. Regulatory loops by which VEGF controls the survival of HSCs have been described 78 , as well as cross-talk between hematopoietic, endothelial and mesenchymal cells in embryonic as well as adult hematopoietic environments. It remains unclear whether the observed decreased BM vascularization in AA is instrumental in the bone marrow failure process or rather another consequence of the profoundly disturbed hematopoiesis with reduced content of cytokine producing cells.

    Nevertheless, such a strongly impaired BM microenvironment is likely to sustain hematopoietic defects and furthermore delay hematopoietic regeneration even after the causative agent was removed e.

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    Taken together, a disturbed microenvironment with abnormal functioning MSCs is, next to BM hypoplasia, a further hallmark in patients with acquired AA. MSCs have been utilized in the settings of therapy for other disorders due to their immunomodulatory and proliferative functions; e. However, larger studies are needed to evaluate the utility of MSCs further.

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    7. In a recent study by Yue et al. All patients achieved sustained, full donor chimerism, and the median time of myeloid recovery and platelet engraftment was 13 days, respectively. MSCs and other non-hematopoietic cells present in the BM vs. PB as stem cell source, may contribute to niche regeneration post-transplantation by a providing transient VEGF and cytokine support, b enhancing immune suppression and possibly but less probable by c providing stable niche engraftment of donor-derived niche cells.

      Considering that multiple progenitor cells, as well as HSCs are enriched in transplanted PBSC and BM 68 — 70 , 85 there may be several possible mechanisms to explain the restoration of the BM niche which include transient engraftment of cytokine producing non-hematopoietic BM cells that promote niche restoration and thereby facilitate hematopoietic regeneration 69 — The cross-talk between the microenvironment and the defective hematopoietic compartment may significantly contribute to the disrupted hematopoiesis and delayed hematopoietic regeneration commonly observed in AA patients. There are several in vitro and in vivo studies indicating quantitative as well as qualitative mesenchymal stromal alterations in patients with AA and, respectively, genetic BMF, which may be pathogenetically involved in the clinical evolution of the disease.

      Further, studies are needed to examine the importance of microenvironment changes in the acquired AA pathogenesis, progression and response to therapy. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

      Luzzatto L, Risitano AM. Advances in understanding the pathogenesis of acquired aplastic anaemia.


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