Inducible Sbds deletion impairs bone marrow niche capacity to engraft donor bone marrow after transplantation

Bone marrow (BM) niche-derived signals are critical for facilitating engraftment after hematopoietic stem cell (HSC) transplantation (HSCT). HSCT is required for restoration of hematopoiesis in patients with inherited BM failure syndromes (iBMFSs). Shwachman-Diamond syndrome (SDS) is a rare iBMFS as...

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Bibliographic Details
Published in:	Blood advances 2022-01, Vol.6 (1), p.108-120
Main Authors:	Zha, Ji, Kunselman, Lori K., Xie, Hongbo M., Ennis, Brian, Shah, Yash B., Qin, Xia, Fan, Jian-Meng, Babushok, Daria V., Olson, Timothy S.
Format:	Article
Language:	eng
Subjects:	Animals Bone Marrow - metabolism Endothelial Cells Gene Deletion Hematopoiesis - genetics Hematopoietic Stem Cell Transplantation Humans Mice Proteins - genetics Proteins - metabolism Shwachman-Diamond Syndrome - genetics Shwachman-Diamond Syndrome - surgery Transplantation Transplantation Conditioning
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Summary:	Bone marrow (BM) niche-derived signals are critical for facilitating engraftment after hematopoietic stem cell (HSC) transplantation (HSCT). HSCT is required for restoration of hematopoiesis in patients with inherited BM failure syndromes (iBMFSs). Shwachman-Diamond syndrome (SDS) is a rare iBMFS associated with mutations in SBDS. Previous studies have demonstrated that SBDS deficiency in osteolineage niche cells causes BM dysfunction that promotes leukemia development. However, it is unknown whether BM niche defects caused by SBDS deficiency also impair efficient engraftment of healthy donor HSC after HSCT, a hypothesis that could explain morbidity noted after clinical HSCT for patients with SDS. Here, we report a mouse model with inducible Sbds deletion in hematopoietic and osteolineage cells. Primary and secondary BM transplantation (BMT) studies demonstrated that SBDS deficiency within BM niches caused poor donor hematopoietic recovery and specifically poor HSC engraftment after myeloablative BMT. We have also identified multiple molecular and cellular defects within niche populations that are driven by SBDS deficiency and are accentuated by or develop specifically after myeloablative conditioning. These abnormalities include altered frequencies of multiple niche cell subsets, including mesenchymal lineage cells, macrophages, and endothelial cells; disruption of growth factor signaling, chemokine pathway activation, and adhesion molecule expression; and p53 pathway activation and signals involved in cell cycle arrest. Taken together, this study demonstrates that SBDS deficiency profoundly impacts recipient hematopoietic niche function in the setting of HSCT, suggesting that novel therapeutic strategies targeting host niches could improve clinical HSCT outcomes for patients with SDS. •Induction of Sbds deficiency in recipient BM niche cells impairs efficient engraftment of healthy donor HSC after transplantation.•SBDS deficiency impairs multiple cellular signaling pathways in post-myeloablation marrow niches critical for restoration of hematopoiesis. [Display omitted]
ISSN:	2473-9529 2473-9537