From the  local response point of view, we have investigated the role of various cell populations during bone regeneration. Among the cell populations in DO regenerate, mesenchymal stem/stromal cells (MSCs) which are responsible for bone regeneration and immune cells (particularly macrophages) which maintains the microenvironment have attracted our attention. Previously, we have optimized the therapeutic time points for stem cell therapy to achieve early bone consolidation in the bone lengthening rat model. In addition, we found an equivalent effect of autologous and allogeneic BMSCs on bone consolidation in this model. Recently, we identified a PSCs-like cell population in the induced membrane (IM) of patients subjected to IM technique, showing an equivalent osteogenic differentiation potential and bone healing outcomes with PSCs when combined with decellularized bone matrix. Recent evidence from lineage tracing studies suggests that periosteam-derived stem/stromal cells (PSCs) mediated bone formation may dominantly contribute to bone defect healing. Current findings indicate that PSCs had a promising effect on promoting bone regeneration in a periosteam-removal DO model, while bone marrow derived MSCs were unable to effectively repair bone defects. We also identified the mechanoresponsive PI3K-AKT signaling pathway as a key mechanism by which PSCs contribute to bone regeneration during DO.

Project 2: Role of mechanoresponsive immune cells in bone regeneration

Previously, we have investigated a positive effect of Staphylococcal enterotoxin type C II (SEC2), a kind of T cell activator, on bone homeostasis. We have successfully identified IFN-γ as a key cytokine from T cells in mediating osteoblast differentiation. We have further explored the cellular microenvironment of the DO regenerate, with a focus on the role of T cell and macrophage subsets in bone regeneration. By using single cell RNA-seq technique, we successfully identified innate lymphoid cells (ILC1) as a novel T cell subset present in high proportions in the DO regenerate, and predicted a close interaction between ILC1 and osteoblasts. 

Macrophages are critically involved in bone repair, with a brief inflammatory (M1)-dominated phase, followed by a transition to anti-inflammatory (M2)-dominant phenotype. A timely shift to M2 polarization is essential for tissue repair. Researchers have found that mechanical stimulation can determine the fate of immune cells, particularly macrophages, participating in various disease progression and tissue regeneration. Notably, my team’s recent work has addressed the mechanism of mechanically-induced M2 polarization of macrophages during DO, demonstrating the regulatory role of the focal adhesive Integrin-SRC-STAT6 signaling pathway. Through scRNA seq, we have successfully identified a certain macrophage subpopulation responded to mechanical stress, which then subsequently promoting bone regeneration. We are now conducting further mechanistic research by investigating the mechanoresponsive metabolic reprogramming and epigenetic modification in the macrophages during DO procedure.

Project 3: Skeletal interoception during bone regeneration

Recently, the crosstalk between skeletal system and nervous system has been intensively investigated. Central and peripheral nervous systems have been found play a key role in regulating bone homeostasis, diseases and repair. Skeletal interoception could be one of the links between the skeletal and nervous systems. A better understanding of the skeletal interoception may pave a road to interpret the interactions between skeletal and nervous systems, further to tackle unsolved clinical challenges in both systems. Although innervation in DO regenerated tissue and fracture callus has been addressed in previous studies, skeletal interoception in DO remains largely unknown. To address these fundamental questions, we have conducted preliminary studies.

Project 4: Cartilage tissue regeneration and osteoarthritis treatment

Another theme of the team research is development of bioactive scaffolds and “smart” hydrogels. These materials are engineered to mimic the cartilage extracellular matrix, providing a supportive microenvironment for MSCs. Our studies often explore how these biomaterials can be functionalized to promote chondrogenic differentiation and improve the mechanical integration of engineered tissue with host bone. Notably, the lab’s recent work delves into the mechanobiology of the joint, we aim to understand how biophysical and biochemical cues can be harnessed to trigger endogenous regeneration.