| Mice |
Role of macrophages in AA |
- Depleting macrophages or abrogating IFN-γ signaling in macrophages did not impair T-cell activation or IFN-γ production in the BM but rescued HSCs - Macrophages are not required for induction of IFN-γ in SAA and rather act as sensors of IFN-γ - Macrophage depletion rescued thrombocytopenia, increased BM megakaryocytes, preserved platelet-primed stem cells, and increased the platelet-repopulating capacity of transplanted HSCs
|
(33) |
| Mice, human |
TNF-α from host macrophages and TNF-αR expressed on donor T cells are critical in the pathogenesis of murine immune-mediated BM failure - AA patients have higher frequencies of TNF-α-producing CD16+CD68+ macrophages in the BM than do healthy donors |
- Infusion of TNF-α−/− donor LN cells into CByB6F1 recipients mice or injection of FVB LN cells into TNF-αR−/− recipients both induced BM failure, with marked increases in plasma IFN-γ and TNF-α levels - In TNF-α−/− recipients, BM damage was attenuated, suggesting that TNF-α of host origin was essential for immune destruction of hematopoiesis - Depletion of host macrophages before LN injection reduced T-cell IFN-γ levels and reduced BM damage, while injection of recombinant TNF-α into FVB-LN cell-infused TNF-α−/− recipients increased T-cell IFN-γ expression and accelerated BM damage - Infusion of TNF-αR−/− donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-γ production, and alleviated BM destruction - In AA patients, TNF-α-producing macrophages in the BM were more frequent than in healthy donors
|
(32) |
| Mice |
ROS generation is associated with BM failure in AA |
- Increased ROS and disruption of hematopoietic niche under aplastic stress - Decline of stromal components and deregulation of Notch-1/ Jagged-1 signaling axis in aplastic marrow - Altered DNA methylation and H-3 phosphorylation status associated with redox imbalance in aplastic marrow
|
(41) |
| Human |
VEGF-Notch signaling pathway |
- Lower expression of VEGF, VEGFR, Notch-1, Jagged1, Delta-like1, and hes1 was revealed in AA BM tissues and AA MSCs - The intervention of DAPT (a γ-secretase inhibitor) significantly inhibited proliferation, and promoted the apoptosis and adipogenic differentiation of AA MSCs, while VEGF intervention exhibited opposite results - The proliferation, migration, and angiogenesis of HUVECs were significantly promoted by normal BM-MSCs, while inhibited by VEGF/Notch-1 shRNA transfected BM-MSCs
|
(42) |
| Human, mice |
Effect of CD106 and NF-κB in BM failure of AA |
- BM-MSCs from AA patients exhibited downregulation of the CD106 gene (VCAM1) and low expression of CD106 in vitro - CD106+ MSCs from both AA patients and healthy controls had increased potential for in vitro capillary tube-like formation and in vivo vasculogenesis compared with CD106− MSCs - CD106+ MSCs from both AA patients and healthy controls more strongly supported in vitro growth and in vivo engraftment of CD34+ cells in NOD/SCID mice than CD106− MSCs - Expression of NF-κB was decreased in AA MSCs, and NF-κB regulated the CD106 gene (VCAM1) which supported hematopoiesis
|
(43) |
| Human |
Vascular and perivascular niches are numerically restored, but the endosteal niche remains numerically impaired in patients with AA after allo-HCT |
|
(44) |
| Human |
AA is associated with impaired hematopoietic stem cell niches |
|
(45) |
| Human |
The biological characteristics of AA MSC are different from those of control MSC and their in vitro haemopoiesis -supporting ability is significantly reduced |
- AA MSC presented typical morphology and distinctive mesenchymal markers, stromal formation was reduced, with 50% of BM samples failing to produce adherent layers - Their proliferative and clonogenic capacity was markedly decreased and the ability to sustain haemopoiesis was significantly reduced, as assessed by total cell proliferation and clonogenic potential of HSC
|
(46) |
| Human, mice |
BM-MSCs from patients with AA do not have impaired functional and immunological properties, suggesting that they do not contribute to the pathogenesis of the disease |
- MSCs cultures can be established from the BM of AA patients and display the same phenotype and differentiation potential as their counterparts from normal BM - MSCs from AA patients support the in vitro homeostasis and the in vivo repopulating function of CD34+ cells, and maintain their immunosuppressive and anti-inflammatory properties
|
(47) |
| Human |
Gene expression profile of BM-MSCs confirmed the abnormal biological properties and provided significant evidence for the possible mechanism of the destruction of the BM microenvironment in AA |
- BM-MSCs from AA patients showed aberrant morphology, decreased proliferation and clonogenic potential and increased apoptosis compared to controls - BM-MSCs from AA patients were susceptible to be induced to differentiate into adipocytes but more difficult to differentiate into osteoblasts - A large number of genes implicated in cell cycle, cell division, proliferation, chemotaxis and hematopoietic cell lineage showed markedly decreased expression in BM-MSCs from AA patients - Conversely, more related genes with apoptosis, adipogenesis and immune response showed increased expression in BM-MSCs from AA patients
|
(48) |
