Pathogenesis of Acquired Aplastic Anemia and the Role of the Bone Marrow Microenvironment

Medinger, Michael; Drexler, Beatrice; Lengerke, Claudia; Passweg, Jakob

doi:10.3389/fonc.2018.00587

Cited by 62 publications

(52 citation statements)

References 86 publications

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“…This study suggested that the destruction of the functionally active HSC, upon exposure to IFNγ, is immune mediated through activated cytotoxic T cells (14). Additionally, it has been suggested that immune-mediated destruction of HSC leads to BMF in aplastic anemia (9). However, in the current study in the context of immune-deficient NSG mice, the lack of functional T, B and NK cells did not attenuate TIRAP-mediated BMF.…”

Section: Discussioncontrasting

confidence: 65%

See 1 more Smart Citation

TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

Ibrahim

Gopal

Fuller

et al. 2020

Preprint

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Activation of inflammatory pathways is associated with bone marrow failure syndromes, but how specific molecules impact on the marrow microenvironment is not well elucidated. We report a novel role for the miR-145 target, Toll/Interleukin-1 receptor domain containing adaptor protein (TIRAP), in driving bone marrow failure. We show that TIRAP is overexpressed in various types of myelodysplastic syndromes (MDS), and suppresses all three major hematopoietic lineages.. Constitutive expression of TIRAP in hematopoietic stem/progenitor cells (HSPC) promotes upregulation of Ifnγ, leading to bone marrow failure. Myelopoiesis is suppressed through Ifnγ-Ifnγr-mediated release of the alarmin, Hmgb1, which disrupts the marrow endothelial niche. Deletion of Ifnγ or Ifnγr blocks Hmgb1 release and is sufficient to reverse the endothelial defect and prevent myelosuppression. In contrast, megakaryocyte and erythroid production is repressed independently of the Ifnγ receptor. Contrary to current dogma, TIRAP-activated Ifnγ-driven marrow suppression is independent of T cell function or pyroptosis.In the absence of Ifnγ, TIRAP drives myeloproliferation, implicating Ifnγ in suppressing the transformation of bone marrow failure syndromes to myeloid malignancy. These findings reveal novel, non-canonical roles of TIRAP, Hmgb1 and Ifnγ function in the marrow microenvironment,and provide insight into the pathophysiology of preleukemic syndromes.AGGGTCTACGGGGCAATTT; rev-ACAGTCCGTTTCCGGAGTT); mFasL (for-TTTAACAGGGAACCCCCACT; rev-GATCACAAGGCCACCTTTCT); mIfna (for-GACTTTGGATTCCCGCAGGAGAAG; rev-CTGCATCAGACAGCCTTGCAGGTC); mIfnab (for-CCTGCTGGCTGTGAGGAAAT; rev-CTCACTCAGACTTGCCAGCA); mHmgb1 (for-GTTCTGAGTACCGCCCCAAA; rev-GTAGGCAGCAATATcCTTCTC); mIL-4 (for-TTGAACGAGGTCACAGGAGA; rev-AAATATGCGAAGCACCTTGG); mIL-17a (for-CGCAAAAGTGAGCTCCAGA; rev-TGAGCTTCCCAGATCACAGA); mIL-1rn (for-GTGAGACGTTGGAAGGCAGT; rev-GCATCTTGCAGGGTCTTTTC); mTNFSF11 (for-GACTCCATGAAAACGCAGGT; rev-CCCACAATGTGTTGCAGTTC); mIL-13 (for-TGTGTCTCTCCCTCTGACCC; rev-CACACTCCATACCATGCTGC); mIL-1a (for-AGCGCTCAAGGAGAAGACC; rev-CCAGAAGAAAATGAGGTCGG); mIL-27 (for-GTGACAGGAGACCTTGGCTG; rev-AGCTCTTGAAGGCTCAGGG); mCSF1 (for-CCAGGATGAGGACAGACAGG; rev-GGTAGTGGTGGATGTTCCCA); mCCL2 (for-AGGTCCCTGTCATGCTTCTG; rev-GGGATCATCTTGCTGGTGAA); mIL-23a (for-TTGTGACCCACAAGGACTCA; rev-AGGCTCCCCTTTGAAGATGT); mIfna13 (for-CTTTGGATTCCCACAGGAGA; rev-TTCCATGCAGCAGATGAGTC); mIfna2 (for-GCAGATCCAGAAGGCTCAAG; rev-GGTGGAGGTCATTGCAGAAT); mGAPDH (for-TGCAGTGGCAAAGTGGAGAT; rev-TTTGCCGTGAGGAGTCATA); hIFNγR1 (for-CCAGGGTTGGACAAAAAGAA; rev-CGGGATCATAATCGACTTCC); hIFNγR2 (for-TGACAATGCCTTGGTTTCAA; rev-ATCAGCGATGTCAAAGGGAG); mCamp (for-GCTGTGGCGGTCACTATCAC; rev-TGTCTAGGGACTGCTGGTTGA); mTmsb10 (for-CCGGACATGGGGGAAATCG; rev-CCTGTTCAATGGTCTCTTTGGTC); mTmsb4x (for-ATGTCTGACAAACCCGATATGGC; rev-CCAGCTTGCTTCTCTTGTTCA); mAnxa6 (for-

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Section: Discussioncontrasting

confidence: 65%

“…Dysregulation of immune responses has been implicated in MDS and other BMF disorders (5,(7)(8)(9)(10). A pro-inflammatory milieu and sensitivity of hematopoietic stem/progenitor cells (HSPC) to inflammatory cytokines such as TNF-α, IL-6 and IFNγ have been shown to suppress normal hematopoiesis (5,11).…”

Section: Introductionmentioning

confidence: 99%

TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

Ibrahim

Gopal

Fuller

et al. 2020

Preprint

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“…Mesenchymal stem/stromal cells (MSCs) are heterogeneous populations capable of multipotential differentiation together with hematopoietic supporting and immunosuppressive properties [9][10][11]. MSCs have been wildly used in preclinical and clinical studies for disease remodeling including acute-on-chronic liver failure, diabetes, Crohn's disease, and acquired AA [9,[12][13][14][15][16]. Generally, as the key component in the microenvironment, MSCs serve as a potential supplementary alternative for refractory AA treatment and have exhibited unexceptionably therapeutic effect mainly through transdifferentiation, immunomodulatory activity, autocrine, and paracrine together with providing an ideal niche [17,18].…”

Section: Introductionmentioning

confidence: 99%

“…Generally, as the key component in the microenvironment, MSCs serve as a potential supplementary alternative for refractory AA treatment and have exhibited unexceptionably therapeutic effect mainly through transdifferentiation, immunomodulatory activity, autocrine, and paracrine together with providing an ideal niche [17,18]. However, the dysfunction and pathophysiology of MSCs during acquired AA is still obscure [1,14]. As mentioned above, our team and Hamzic et al have identified the MSC's involvement in the dysfunction of HSCs and immunological reconstitution in patients with AA [19,20].…”

Section: Introductionmentioning

confidence: 99%

Multifaceted characterization of the signatures and efficacy of mesenchymal stem/stromal cells in acquired aplastic anemia

et al. 2020

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Background: Longitudinal studies have verified the pivotal role of mesenchymal stem/stromal cells (MSCs) in the bone marrow microenvironment for hematopoiesis and coordinate contribution to leukemia pathogenesis. However, the precise characteristics and alternation of MSCs during acquired aplastic anemia (AA) remain obscure. Methods: In this study, we originally collected samples from both healthy donors (HD) and AA patients to dissect the hematological changes. To systematically evaluate the biological defects of AA-derived MSCs (AA-MSCs), we analyzed alterations in cellular morphology, immunophenotype, multi-lineage differentiation, cell migration, cellular apoptosis, and chromosome karyocyte, together with the immunosuppressive effect on the activation and differentiation of lymphocytes. With the aid of whole genome sequencing and bioinformatic analysis, we try to compare the differences between AA-MSCs and HD-derived MSCs (HD-MSCs) upon the molecular genetics, especially the immune-associated gene expression pattern. In addition, the efficacy of umbilical cord-derived MSC (UC-MSC) transplantation on AA mice was evaluated by utilizing survivorship curve, histologic sections, and blood cell analyses. Results: In coincidence with the current reports, AA patients showed abnormal subsets of lymphocytes and higher contents of proinflammatory cytokines. Although with similar immunophenotype and chromosome karyotype to HD-MSCs, AA-MSCs showed distinguishable morphology and multiple distinct characteristics including genetic properties. In addition, the immunosuppressive effect on lymphocytes was significantly impaired in AA-MSCs. What is more, the cardinal symptoms of AA mice were largely rescued by systemic transplantation of UC-MSCs. Conclusions: Herein, we systematically investigated the signatures and efficacy of MSCs to dissect the alterations occurred in AA both at the cellular and molecular levels. Different from HD-MSCs, AA-MSCs exhibited multifaceted defects in biological characteristics and alterative molecular genetics in the whole genome. Our findings have provided systematic and overwhelming new evidence for the defects of AA-MSCs, together with effectiveness assessments of UC-MSCs on AA as well.

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“…Aplastic anemia (AA) is a rare disease, caused by bone marrow (BM) aggression resulting in hypo or aplastic BM with precocious fat replacement and consequently to peripheral blood pancytopenia [1,2]. The autoimmunity process in AA occurs due to the activation of the oligoclonal cytotoxic T cells that will lead the hematopoietic cells to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Alternative Immune-Mediated-Based Methods in the Aplastic Anemia Treatment

Gonzaga¹,

Policiquio²,

Wenceslau³

et al. 2021

Human Blood Group Systems and Haemoglobinopathies

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Acquired aplastic anemia (AA) is characterized by partial or total bone marrow (BM) destruction resulting in pancytopenia. Most of the acquired AA is the result of autoimmune condition the imbalance between T-regulatory cells (Treg), abnormal cytokines production and cytotoxic T cells activation, leading to the hematopoietic stem cells (HSCs) death. The first-line treatment is given by HSC transplant, but some patients did not respond to the treatment. Therefore, new technologies need to treat AA nonresponder patients. Studies are in progress to test the efficacy of stem cell-based therapeutic as mesenchymal stem cells (MSCs), which confer low immunogenicity and are reliable allogeneic transplants in refractory severe AA cases. Furthermore, MSCs comprise the BM stromal niche and have an important role in supporting hematopoiesis by secreting regulatory cytokines, providing stimulus to natural BM microenvironment. In addition, MSCs have immunomodulatory property and are candidates for efficient supporting AA therapy.

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Pathogenesis of Acquired Aplastic Anemia and the Role of the Bone Marrow Microenvironment

Cited by 62 publications

References 86 publications

TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

Multifaceted characterization of the signatures and efficacy of mesenchymal stem/stromal cells in acquired aplastic anemia

Alternative Immune-Mediated-Based Methods in the Aplastic Anemia Treatment

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