Browsing by Author "Hart, David A"

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    Characterization of Mesenchymal Stem Cell-Like Cells Derived From Human iPSCs via Neural Crest Development and Their Application for Osteochondral Repair
    (2017-05-18) Chijimatsu, Ryota; Ikeya, Makoto; Yasui, Yukihiko; Ikeda, Yasutoshi; Ebina, Kosuke; Moriguchi, Yu; Shimomura, Kazunori; Hart, David A; Yoshikawa, Hideki; Nakamura, Norimasa
    Mesenchymal stem cells (MSCs) derived from induced pluripotent stem cells (iPSCs) are a promising cell source for the repair of skeletal disorders. Recently, neural crest cells (NCCs) were reported to be effective for inducing mesenchymal progenitors, which have potential to differentiate into osteochondral lineages. Our aim was to investigate the feasibility of MSC-like cells originated from iPSCs via NCCs for osteochondral repair. Initially, MSC-like cells derived from iPSC-NCCs (iNCCs) were generated and characterized in vitro. These iNCC-derived MSC-like cells (iNCMSCs) exhibited a homogenous population and potential for osteochondral differentiation. No upregulation of pluripotent markers was detected during culture. Second, we implanted iNCMSC-derived tissue-engineered constructs into rat osteochondral defects without any preinduction for specific differentiation lineages. The implanted cells remained alive at the implanted site, whereas they failed to repair the defects, with only scarce development of osteochondral tissue in vivo. With regard to tumorigenesis, the implanted cells gradually disappeared and no malignant cells were detected throughout the 2-month follow-up. While this study did not show that iNCMSCs have efficacy for repair of osteochondral defects when implanted under undifferentiated conditions, iNCMSCs exhibited good chondrogenic potential in vitro under appropriate conditions. With further optimization, iNCMSCs may be a new source for tissue engineering of cartilage.
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    Effect of a prebiotic supplement on knee joint function, gut microbiota, and inflammation in adults with co-morbid obesity and knee osteoarthritis: study protocol for a randomized controlled trial
    (2021-04-07) Fortuna, Rafael; Hart, David A; Sharkey, Keith A; Schachar, Rachel A; Johnston, Kelly; Reimer, Raylene A
    Abstract Background Osteoarthritis (OA) is a chronic and painful condition where the articular cartilage surfaces progressively degenerate, resulting in loss of function and progressive disability. Obesity is a primary risk factor for the development and progression of knee OA, defined as the “metabolic OA” phenotype. Metabolic OA is associated with increased fat deposits that release inflammatory cytokines/adipokines, thereby resulting in systemic inflammation which can contribute to cartilage degeneration. There is currently no cure for OA. Prebiotics are a type of dietary fiber that can positively influence gut microbiota thereby reducing systemic inflammation and offering protection of joint integrity in rodents. However, no human clinical trials have tested the effects of prebiotics in adults with obesity suffering from knee OA. Therefore, the purpose of this double-blind, placebo-controlled, randomized trial is to determine if prebiotic supplementation can, through positive changes in the gut microbiota, improve knee function and physical performance in adults with obesity and knee OA. Methods Adults (n = 60) with co-morbid obesity (BMI > 30 kg/m2) and knee OA (Kellgren-Lawrence grade II–III) will be recruited from the Alberta Hip and Knee Clinic and the Rocky Mountain Health Clinic and surrounding community of Calgary, Canada, and randomized (stratified by sex, BMI, and age) to prebiotic (oligofructose-enriched inulin; 16 g/day) or a calorie-matched placebo (maltodextrin) for 6 months. Anthropometrics, performance-based tests, knee pain, serum inflammatory markers and metabolomics, quality of life, and gut microbiota will be assessed at baseline, 3 months, 6 months (end of prebiotic supplementation), and 3 months following the end of the prebiotic supplementation. Clinical significance There is growing pressure on health care systems for aggressive OA treatment such as total joint replacement. Less aggressive, yet effective, conservative treatment options have the potential to address the growing prevalence of co-morbid obesity and knee OA by delaying the need for joint replacement or ideally preventing its need altogether. The results of this clinical trial will provide the first evidence regarding the efficacy of prebiotic supplementation on knee joint function and pain in adults with obesity and knee OA. If successful, the results may provide a simple, safe, and easy to adhere to intervention to reduce knee joint pain and improve the quality of life of adults with co-morbid knee OA and obesity. Trial registration Clinical Trials.gov NCT04172688 . Registered on 21 November 2019.
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    Quantifying the Effects of Different Treadmill Training Speeds and Durations on the Health of Rat Knee Joints
    (2018-04-02) Rios, Jaqueline L; Boldt, Kevin R; Mather, James W; Seerattan, Ruth A; Hart, David A; Herzog, Walter
    Abstract Background Walking and running provide cyclical loading to the knee which is thought essential for joint health within a physiological window. However, exercising outside the physiological window, e.g. excessive cyclical loading, may produce loading conditions that could be detrimental to joint health and lead to injury and, ultimately, osteoarthritis. The purpose of this study was to assess the effects of a stepwise increase in speed and duration of treadmill training on knee joint integrity and to identify the potential threshold for joint damage. Methods Twenty-four Sprague-Dawley rats were randomized into four groups: no exercise, moderate duration, high duration, and extra high duration treadmill exercise. The treadmill training consisted of a 12-week progressive program. Following the intervention period, histologic serial sections of the left knee were graded using a modified Mankin Histology Scoring System. Mechanical testing of the tibial plateau cartilage and RT-qPCR analysis of mRNA from the fat pad, patellar tendon, and synovium were performed for the right knee. Kruskal-Wallis testing was used to assess differences between groups for all variables. Results There were no differences in cartilage integrity or mechanical properties between groups and no differences in mRNA from the fat pad and patellar tendon. However, COX-2 mRNA levels in the synovium were lower for all animals in the exercise intervention groups compared to those in the no exercise group. Conclusions Therefore, these exercise protocols did not exceed the joint physiological window and can likely be used safely in aerobic exercise intervention studies without affecting knee joint health.
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    Relationship between inflammation, the gut microbiota, and metabolic osteoarthritis development: studies in a rat model
    (2016) Herzog, Walter; Collins, Kelsey H; Paul, Heather A; Reimer, Raylene A; Seerattan, Ruth A; Hart, David A
    Western-type diets, high in fat and sugars, lead to obesity. Obesity in turn is associated with chronic inflammation, and thought to be a risk factor for the onset and increased rate of progression of metabolic osteoarthritis (OA) in joints. Emerging evidence suggests that intrinsic inflammatory mediators secreted by body fat, or adipose tissue, including cytokines, adipokines, and advanced glycation end products, may be sufficient to lead to onset and progression of OA. It appears that these obesity-associated, intrinsic inflammatory factors define a metabolic subtype of osteoarthritis. Characterizing the factors that comprise this unhealthy metabolic phenotype is critical to understanding the influence of obesity on OA. Furthermore, establishing the “indirect” role of the microbiota and the gut is required to fully understand the initiators and drivers of metabolic OA.
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    Scaffold-free tissue engineering for injured joint surface restoration
    (2018-01-05) Shimomura, Kazunori; Ando, Wataru; Fujie, Hiromichi; Hart, David A; Yoshikawa, Hideki; Nakamura, Norimasa
    Abstract Articular cartilage does not heal spontaneously due to its limited healing capacity, and thus effective treatments for cartilage injuries has remained challenging. Since the first report by Brittberg et al. in 1994, autologous chondrocyte implantation (ACI) has been introduced into the clinic. Recently, as an alternative for chondrocyte-based therapy, mesenchymal stem cell (MSC)-based therapy has received considerable research attention because of the relative ease in handling for tissue harvest, and subsequent cell expansion and differentiation. In this review, we discuss the latest developments regarding stem cell-based therapies for cartilage repair, with special focus on recent scaffold-free approaches.