Abstract Number: PB0956
Meeting: ISTH 2021 Congress
Background: Megakaryocytes (MKs) in the bone marrow (BM) are exposed to extracellular matrix (ECM) proteins to prevent premature platelet release. Total body irradiation (TBI), which is widely used as a conditioning regimen for hematopoietic stem cell transplantation (HSCT), leads to ECM-remodeling by matrix-metalloproteinase MMP9, preceding a massive vasodilation, reduction in MK numbers and thrombocytopenia. Prolonged thrombocytopenia is a frequent complication after HSCT, which is associated with poor prognosis and increased mortality. The underlying mechanisms of long-lasting thrombocytopenia after HSCT are still unknown.
Aims: This study aims to analyze the role of MMP9 in BM remodeling after irradiation and MK engraftment after HSCT.
Methods: Mouse femur sections were stained and subjected to confocal immunofluorescence microscopy to map BM sinusoids, MKs, and ECM proteins. MMP expression and activity was assessed by immunoblot analysis, gelatin-zymography, in situ zymography, and live-cell zymography. Studies were performed using MMP9-/- mice and littermate controls. Ubiquitously dsRed-expressing reporter mice were used as BM donors in HSCT to assess reconstitution of the vasculature and MK engraftment.
Results: Collagen IV is selectively degraded at BM sinusoids after sublethal TBI, while we found specific upregulation of MMP9 activity. This appeared not to drive reduction of MK numbers or platelet counts after TBI. MMP9-/- mice, however, displayed a delayed recovery of irradiation-induced vasodilation indicating a role of MMP9 in vascular remodeling. MMP9-/- mice and wildtype controls showed a similar engraftment capacity with donor-derived MKs and platelets being detectable as early as d4 after HSCT. On d7 vasodilation was still increased in MMP9-/- animals. In the transplanted BM we detected remaining gelatinolytic activity in MMP9-deficient mice, suggesting compensatory upregulation of other MMP family members besides MMP2.
Conclusions: The findings presented here show that MMP9 plays a minor role for early MK engraftment, but is a modulator of the vasculature, as reflected by a prolonged vasodilation after HSCT.
To cite this abstract in AMA style:Mott K, Semeniak D, Schulze H. The Role of Matrix-metalloproteinase 9 in Bone Marrow Remodeling after Total Body Irradiation and Hematopoietic Stem Cell Transplantation [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/the-role-of-matrix-metalloproteinase-9-in-bone-marrow-remodeling-after-total-body-irradiation-and-hematopoietic-stem-cell-transplantation/. Accessed August 16, 2022.
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