Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by defined factors. However, the low efficiency and slow kinetics of the reprogramming process have hampered progress with this technology. Here we report that a natural compound, vitamin C (Vc), enhances iPSC generation from both mouse and human somatic cells. Vc acts at least in part by alleviating cell senescence, a recently identified roadblock for reprogramming. In addition, Vc accelerates gene expression changes and promotes the transition of pre-iPSC colonies to a fully reprogrammed state. Our results therefore highlight a straightforward method for improving the speed and efficiency of iPSC generation and provide additional insights into the mechanistic basis of the reprogramming process.

OA is now well accepted as a low-grade inflammatory disease affecting the whole joint. In addition to mechanical loading, inflammation (particularly synovitis), contributes significantly to OA. Synovial macrophages act as immune cells and are of critical importance in the symptomology and structural progression of OA. Activated macrophages are regulated by mTOR, NF-kB, JNK, PI3K/Akt and other signaling pathways, and are polarized into either M1 or M2 subtypes in OA synovial tissues, synovial fluid, and peripheral blood. The activation state and the M1/M2 ratio is highly associated with OA severity. Aside from autocrine interactions, paracrine interactions between macrophages and chondrocytes play a vital role in the initiation and development of OA by secreting inflammatory cytokines, growth factors, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs), which lead to subsequent cartilage degradation and destruction. Treatments targeting synovial macrophages relieve pain, and protect from synovitis, cartilage damage, and osteophyte formation during OA development. Macrophage reprogramming of transformation from the M1 to M2 subtype, more than a decrease in the quantity of activated macrophages, appears to be an effective treatment option for OA. This review provides a broad understanding of the contributions of polarized macrophages to joint health and disease. Multifunctional agents with immunomodulatory effects on macrophage reprogramming can skew the inflammatory microenvironment towards a pro-chondrogenic atmosphere, and are thus, potential therapeutic options for the treatment of OA and other immune diseases.

Ever since synovium-derived mesenchymal stem cells (SMSCs) were first identified and successfully isolated in 2001, as a brand new member in MSC families, they have been increasingly regarded as a promising therapeutic cell species for musculoskeletal regeneration, particularly for reconstructions of cartilage, bones, tendons, and muscles. Besides the general multipotency in common among the MSC community, SMSCs excel other sourced MSCs in higher ability of proliferation and superiority in chondrogenesis. This review summarizes the latest advances in SMSC-related studies covering their specific isolation methodologies, biological insights, and practical applications in musculoskeletal therapeutics of which an emphasis is cast on engineered chondrogenesis.

Precise coordination of cell growth, proliferation and differentiation is essential for the development of multicellular organisms. Here, we report that although the mechanistic target of rapamycin complex 1 (mTORC1) activity is required for chondrocyte growth and proliferation, its inactivation is essential for chondrocyte differentiation. Hyperactivation of mTORC1 via TSC1 gene deletion in chondrocytes causes uncoupling of the normal proliferation and differentiation programme within the growth plate, resulting in uncontrolled cell proliferation, and blockage of differentiation and chondrodysplasia in mice. Rapamycin promotes chondrocyte differentiation and restores these defects in mutant mice. Mechanistically, mTORC1 downstream kinase S6K1 interacts with and phosphorylates Gli2, and releases Gli2 from SuFu binding, resulting in nuclear translocation of Gli2 and transcription of parathyroid hormone-related peptide (PTHrP), a key regulator of bone development. Our findings demonstrate that dynamically controlled mTORC1 activity is crucial to coordinate chondrocyte proliferation and differentiation partially through regulating Gli2/PTHrP during endochondral bone development.

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