O-alg-THAM/gel hydrogels functionalized with engineered microspheres based on mesenchymal stem cell secretion recruit endogenous stem cells for cartilage repair.

Lacking self-repair abilities, injuries to articular cartilage can lead to cartilage degeneration and ultimately result in osteoarthritis. Tissue engineering based on functional bioactive scaffolds are emerging as promising approaches for articular cartilage regeneration and repair. Although the use of cell-laden scaffolds prior to implantation can regenerate and repair cartilage lesions to some extent, these approaches are still restricted by limited cell sources, excessive costs, risks of disease transmission and complex manufacturing practices. Acellular approaches through the recruitment of endogenous cells offer great promise for in situ articular cartilage regeneration. In this study, we propose an endogenous stem cell recruitment strategy for cartilage repair. Based on an injectable, adhesive and self-healable o-alg-THAM/gel hydrogel system as scaffolds and a biophysio-enhanced bioactive microspheres engineered based on hBMSCs secretion during chondrogenic differentiation as bioactive supplement, the as proposed functional material effectively and specifically recruit endogenous stem cells for cartilage repair, providing new insights into in situ articular cartilage regeneration.

Bioactive Film-Guided Soft-Hard Interface Design Technology for Multi-Tissue Integrative Regeneration.

Control over soft-to-hard tissue interfaces is attracting intensive worldwide research efforts. Herein, a bioactive film-guided soft-hard interface design (SHID) for multi-tissue integrative regeneration is shown. Briefly, a soft bioactive film with good elasticity matchable to native ligament tissue, is incorporated with bone-mimic components (calcium phosphate cement, CPC) to partially endow the soft-film with hard-tissue mimicking feature. The hybrid film is elegantly compounded with a clinical artificial ligament to act as a buffer zone to bridge the soft (ligament) and hard tissues (bone). Moreover, the bioactive film-decorated ligament can be rolled into a 3D bio-instructive implant with spatial-controllable distribution of CPC bioactive motifs. CPC then promotes the recruitment and differentiation of endogenous cells in to the implant inside part, which enables a vascularized bone growth into the implant, and forms a structure mimicking the biological ligament-bone interface, thereby significantly improving osteointegration and biomechanical property. Thus, this special design provides an effective SHID-guided implant-bioactivation strategy unreached by the traditional manufacturing methods, enlightening a promising technology to develop an ideal SHID for translational use in the future.

Association of hip fractures with cardiometabolic-renal risk factors in Southern Chinese patients with type 2 diabetes - the Hong Kong Diabetes Register.

INTRODUCTION: Diabetes and bone health are closely related. We examined the incidence and risk factors of hip fractures in Chinese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In this prospective cohort, we consecutively enrolled 22,325 adults with T2D above the age of 40 years in the Hong Kong Diabetes Register between 1994 and 2015 with crude hip fracture incidence rate censored in 2017. RESULTS: At baseline, the mean age of this cohort was 60.9 ± 10.5 years (mean duration of diabetes 6 years, 52.4% male). During a mean ± standard deviation (SD) follow-up period of 8.7 ± 5.2 years with 193,553 person-years, 603 patients were hospitalized due to hip fractures with an incidence (95% confidence interval, CI) of 315.1 (290.4-341.3) per 100,000 person-years. On multivariable analysis with competing death risk adjusted, the independent hazard ratios (95% CI) for hip fractures in T2D were 2.01 (1.61-2.51) for female sex, 1.08 (1.07-1.09) for age, 0.93 (0.90-0.95) for body mass index, 1.52 (1.25-1.85) for albuminuria and 1.12 (1.02-1.23) for low density lipoprotein-cholesterol. In men, the 30-day, 1-year and 5-year post-hip fracture mortality rate (95% CI) were 5.8 (2.4-9.1) %, 29.2 (22.3-35.5) % and 65.9 (57.3-72.8) % respectively. The corresponding rates in women were 3.4 (1.6-5.1) %, 18.6 (14.7-22.4) %, and 46.8 (40.9-52.1) %. CONCLUSIONS: Southern Chinese patients with T2D have a high risk of hip fracture associated with suboptimal cardiometabolic-renal risk factors and a high post-fracture mortality rate. The effects of improving modifiable risk factors on bone health warrants further evaluation.

KDM3A and KDM4C Regulate Mesenchymal Stromal Cell Senescence and Bone Aging via Condensin-mediated Heterochromatin Reorganization.

Epigenomic changes and stem cell deterioration are two hallmarks of aging. Accumulating evidence suggest that senescence of mesenchymal stromal cells (MSCs) perpetuates aging or age-related diseases. Here we report that two H3K9 demethylases, KDM3A and KDM4C, regulate heterochromatin reorganization via transcriptionally activating condensin components NCAPD2 and NCAPG2 during MSC senescence. Suppression of KDM3A or KDM4C by either genetic or biochemical approach leads to robust DNA damage response and aggravates cellular senescence, whereas overexpression of KDM3A/KDM4C or NCAPD2 promotes heterochromatin reorganization and blunts DNA damage response. Moreover, MSCs derived from Kdm3a-/- mice exhibit defective chromosome organization and exacerbated DNA damage response, which are associated with accelerated bone aging. Consistently, analysis of human bone marrow MSCs and transcriptome database reveals inverse correlation of KDM3A/KDM4C and/or NCAPD2/NCAPG2 with aging. Taken together, the present finding unveils that H3K9 demethylases function as a surveillance mechanism to restrain DNA damage accumulation in stem cells during aging.

The Use of Cocultured Mesenchymal Stem Cells with Tendon-Derived Stem Cells as a Better Cell Source for Tendon Repair.

The management of tendon tissue injury presents a significant clinical challenge due to the unique properties of tendons. Cell-based therapy provides a new alternative for regenerating functional tendons, such as in tendon rupture repair, but largely remains at the preclinical research stage. A cell source for graft preparation is essential for successful clinic application. In this study, a novel cell coculture system of bone marrow mesenchymal stem cells (BMSCs) and tendon-derived stem cells (TDSCs) was developed and investigated. BMSCs and TDSCs were cultured separately or in combination at ratios of 20:1, 10:1, 5:1, and 1:1 in vitro, and the cocultured cells showed an enhanced proliferation and collagenous protein production. The coculture system promoted tenogenic differentiation with enhanced tenogenic marker gene expression and collagen matrix production, particularly in the groups with a ratio of 1:1. Using a rat patellar tendon window injury model, we demonstrated that the cell sheets formed by cocultured cells promoted tendon healing significantly, compared to those with a single-cell source. Our study suggests that BMSCs and TDSCs cocultured at the 1:1 ratio may be an improved cell source/preparation for tendon tissue engineering.