期刊
BRITISH JOURNAL OF HAEMATOLOGY
卷 182, 期 1, 页码 114-124出版社
WILEY
DOI: 10.1111/bjh.15388
关键词
Shwachman-Diamond syndrome; mesenchymal stromal cells; bone marrow niche; angiogenesis; childhood
类别
资金
- 'Associazione Italiana Sindrome di Shwachman' (AISS)
- 'Associazione Italiana Ricerca sul Cancro' (AIRC)
- Fondazione Matilde Tettamanti
- Comitato Maria Letizia Verga
- Comitato Stefano Verri
Shwachman-Diamond syndrome (SDS) is a rare multi-organ recessive disease mainly characterised by pancreatic insufficiency, skeletal defects, short stature and bone marrow failure (BMF). As in many other BMF syndromes, SDS patients are predisposed to develop a number of haematopoietic malignancies, particularly myelodysplastic syndrome and acute myeloid leukaemia. However, the mechanism of cancer predisposition in SDS patients is only partially understood. In light of the emerging role of mesenchymal stromal cells (MSCs) in the regulation of bone marrow homeostasis, we assessed the ability of MSCs derived from SDS patients (SDS-MSCs) to recreate a functional bone marrow niche, taking advantage of a murine heterotopic MSC transplant model. We show that the ability of semi-cartilaginous pellets (SCPs) derived from SDS-MSCs to generate complete heterotopic ossicles invivo is severely impaired in comparison with HD-MSC-derived SCPs. Specifically, after invitro angiogenic stimuli, SDS-MSCs showed a defective ability to form correct networks, capillary tubes and vessels and displayed a marked decrease in VEGFA expression. Altogether, these findings unveil a novel mechanism of SDS-mediated haematopoietic dysfunction based on hampered ability of SDS-MSCs to support angiogenesis. Overall, MSCs could represent a new appealing therapeutic target to treat dysfunctional haematopoiesis in paediatric SDS patients.
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