Mesenchymal stem cells in ribosomal insufficiency lead to aberrant osteoblastic differentiation and altered hematopoiesis

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterized by macrocytic anemia. In addition to anemia, patients present with skeletal defects and an increased risk of osteosarcoma, suggesting dysregulated bone cell development. We found that ribosomal protein large subunit 11 (RPL11) haploinsufficiency affects bone marrow mesenchymal stem cells (MSCs), which are the precursors of osteoblasts that support lifelong hematopoiesis. Mouse and human DBA MSCs show decreased proliferation due to cytokinesis failure. Bulk RNA sequencing identified that DBA MSCs are enriched in gene sets associated with inflammation and bone remodeling that can affect surrounding hematopoietic cells. RNA sequencing further predicted aberrant bone maturation in DBA MSCs due to downregulation of the YAP pathway. In vitro differentiation assay confirmed that both mouse and human DBA MSCs fail to differentiate into osteoblasts compared with control MSCs. Activation of YAP signaling improved cell proliferation, morphology, and osteoblast differentiation potential in DBA MSCs. Lastly, we identified that DBA MSCs reduce the expansion of healthy hematopoietic stem and progenitor cells (HSPCs) through osteopontin. In contrast, DBA MSCs provide a favorable niche for DBA HSPCs and significantly increase the expansion of multipotent progenitors (MPPs). However, these MPPs have limited differentiation potential and do not mature into subsequent committed progenitors in the bone marrow. Taken together, this study provides an overview of the defective functions of DBA MSCs, informing follow-up studies to advance our understanding of niche-mediated pathogenic hematopoiesis of DBA.