PhD Candidate Brown Univ. Cranston, Rhode Island, United States
Introduction/Rationale: The protein tyrosine phosphatase SHP2, encoded by PTPN11, is ubiquitously expressed and exhibits cellular context-specific effect. Mutations in PTPN11 have been associated with various human diseases, including Noonan syndrome, myeloproliferative neoplasm, and leukemia. Despite extensive research, SHP2’s role in osteogenesis and hematopoiesis is not fully understood. In this study, I hypothesize that SHP2 regulates bone marrow stromal plasticity, where altered function disrupts hematopoietic niches and osteoblast maturation, leading to abnormal hematopoiesis and ossification.
Methods: To test this hypothesis, I used a conditional gene knockout model to ablate SHP2 in O+SPC BM stromal cells. This study examines how SHP2 loss in O+SPCs regulates hematopoiesis and bone homeostasis. Aim 1 assess effects on O+SPC survival, proliferation, differentiation, and organismal outcomes using cell lineage tracing, FACS, EdU labeling, μCT, and histology. Aim 2 employs scRNA-seq to compare transcriptomic profiles between control and SHP2 mutant mice.
Results: We identified SHP2 ablation in O+SPCs leads to defective ossification and BM adipocyte accumulation compared to the control mice. Furthermore, we discovered that mice lacking SHP2 in O+SPCs had skewed hematopoiesis, particularly CLPs, most likely due to changes in hematopoietic progenitor cell niches, resulting in altered B cell frequencies in the bone marrow. Our scRNA-seq profiling data for the BM nucleated fraction revealed a loss of the common lymphoid clusters in the mutant mice.
Conclusion: These findings demonstrate that SHP2 expression in O+SPCs is essential for bone formation and maintaining the cellular composition and function of hematopoietic niches. This work advances our understanding of the bone marrow stromal biology and reveals potential mechanisms by which SHP2 regulates osteogenesis and hematopoietic niche organization.
