Mesenchymal stem cells (MSCs) are partially defined by their ability to differentiate into tissues including bone, cartilage and adipose in vitro, but it is their trophic, paracrine and immunomodulatory functions that may have the greatest therapeutic impact in vivo. Unlike pharmaceutical treatments that deliver a single agent at a specific dose, MSCs are site regulated and secrete bioactive factors and signals at variable concentrations in response to local microenvironmental cues. Significant progress has been made in understanding the biochemical and metabolic mechanisms and feedback associated with MSC response. The anti-inflammatory and immunomodulatory capacity of MSC may be paramount in the restoration of localized or systemic conditions for normal healing and tissue regeneration. Allogeneic MSC treatments, categorized as a drug by regulatory agencies, have been widely pursued, but new studies demonstrate the efficacy of autologous MSC therapies, even for individuals affected by a disease state. Safety and regulatory concerns surrounding allogeneic cell preparations make autologous and minimally manipulated cell therapies an attractive option for many regenerative, anti-inflammatory and autoimmune applications.

Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine

Mesenchymal stem cells (MSCs) within their native environment of the stem cell niche in bone receive biochemical stimuli from surrounding cells. These stimuli likely infl uence how MSCs differentiate to become bone precursors. The ability of MSCs to undergo osteogenic differentiation is well established in vitro; however, the role of the natural cues from bone’s regulatory cells, osteocytes and osteoblasts in regulating the osteogenic differentiation of MSCs in vivo are unclear. In this study we delineate the role of biochemical signalling from osteocytes and osteoblasts, using conditioned media and co-culture experiments, to understand how they direct osteogenic differentiation of MSCs. Furthermore, the synergistic relationship between osteocytes and osteoblasts is examined by transwell co-culturing of MSCs with both simultaneously. Osteogenic differentiation of MSCs was quantified by monitoring alkaline phosphatase (ALP) activity, calcium deposition and cell number. Intracellular ALP was found to peak earlier and there was greater calcium deposition when MSCs were co-cultured with osteocytes rather than osteoblasts, suggesting that osteocytes are more infl uential than osteoblasts in stimulating osteogenesis in MSCs. Osteoblasts initially stimulated an increase in the number of MSCs, but ultimately regulated MSC differentiation down the same pathway. Our novel coculture system confi rmed a synergistic relationship between osteocytes and osteoblasts in producing biochemical signals to stimulate the osteogenic differentiation of MSCs. This study provides important insights into the mechanisms at work within the native stem cell niche to stimulate osteogenic differentiation and outlines a possible role for the use of co-culture or conditioned media methodologies for tissue engineering applications.

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Osteogenic differentiation of mesenchymal stem cells is regulated by osteocyte and osteoblast cells in a simplified bone niche.

https://www.oarsijournal.com/article/S1063-4584(13)00903-5/pdf

Basic science and clinical application of platelet-rich plasma for cartilage defects and osteoarthritis: a review

Osteoarthritis (OA) is a degenerative disease of the connective tissue and progresses with age in the older population or develops in young athletes following sports-related injury. The articular cartilage is especially vulnerable to damage and has poor potential for regeneration because of the absence of vasculature within the tissue. Normal load-bearing capacity and biomechanical properties of thinning cartilage are severely compromised during the course of disease progression. Although surgical and pharmaceutical interventions are currently available for treating OA, restoration of normal cartilage function has been difficult to achieve. Since the tissue is composed primarily of chondrocytes distributed in a specialized extracellular matrix bed, bone marrow stromal cells (BMSCs), also known as bone marrow-derived 'mesenchymal stem cells' or 'mesenchymal stromal cells', with inherent chondrogenic differentiation potential appear to be ideally suited for therapeutic use in cartilage regeneration. BMSCs can be easily isolated and massively expanded in culture in an undifferentiated state for therapeutic use. Owing to their potential to modulate local microenvironment via anti-inflammatory and immunosuppressive functions, BMSCs have an additional advantage for allogeneic application. Moreover, by secreting various bioactive soluble factors, BMSCs can protect the cartilage from further tissue destruction and facilitate regeneration of the remaining progenitor cells in situ. This review broadly describes the advances made during the last several years in BMSCs and their therapeutic potential for repairing cartilage damage in OA.

/pdf/mesenchymal-stem-cells-for-cartilage-repair-in-aoy0hus6jp.pdf

Mesenchymal stem cells for cartilage repair in osteoarthritis

Platelet-rich plasma (PRP) is an autologous concentrated cocktail of growth factors and inflammatory mediators, and has been considered to be potentially effective for cartilage repair. In addition, the fibrinogen in PRP may be activated to form a fibrin matrix to fill cartilage lesions, fulfilling the initial requirements of physiological wound healing. The anabolic, anti-inflammatory and scaffolding effects of PRP based on laboratory investigations, animal studies, and clinical trials are reviewed here. In vitro, PRP is found to stimulate cell proliferation and cartilaginous matrix production by chondrocytes and adult mesenchymal stem cells (MSCs), enhance matrix secretion by synoviocytes, mitigate IL-1β-induced inflammation, and provide a favorable substrate for MSCs. In preclinical studies, PRP has been used either as a gel to fill cartilage defects with variable results, or to slow the progression of arthritis in animal models with positive outcomes. Findings from current clinical trials suggest that PRP may have the potential to fill cartilage defects to enhance cartilage repair, attenuate symptoms of osteoarthritis and improve joint function, with an acceptable safety profile. Although current evidence appears to favor PRP over hyaluronan for the treatment of osteoarthritis, the efficacy of PRP therapy remains unpredictable owing to the highly heterogeneous nature of reported studies and the variable composition of the PRP preparations. Future studies are critical to elucidate the functional activity of individual PRP components in modulating specific pathogenic mechanisms.

/pdf/biology-of-platelet-rich-plasma-and-its-clinical-application-4iiclb2gey.pdf

Biology of platelet-rich plasma and its clinical application in cartilage repair

Objective:To test the hypothesis that platelet-rich fibrin glue (PR-FG) can be used clinically as a scaffold to deliver autologous culture-expanded bone marrow mesenchymal stem cells (BM-MSCs) for cartilage repair and to report clinical results 1 y after implantation of MSCs PR-FG.Patients and Methods:Autologous BM-MSCs were culture expanded, placed on PR-FG intraoperatively, and then transplanted into 5 full-thickness cartilage defects of femoral condyles of 5 patients and covered with an autologous periosteal flap. Patients were evaluated clinically at 6 and 12 mo by the Lysholm and Revised Hospital for Special Surgery Knee (RHSSK) scores and radiographically by x-rays and magnetic resonance imaging (MRI) at the same time points. Repair tissue in 2 patients was rated arthroscopically after 12 mo using the International Cartilage Repair Society (ICRS) Arthroscopic Score.Study Design:Case series; level of evidence 4.Results:All patients’ symptoms improved over the follow-up period of 12 mo. Average Lyshol...

http://journals.sagepub.com/doi/pdf/10.1177/1947603510366027

The Clinical Use of Human Culture–Expanded Autologous Bone Marrow Mesenchymal Stem Cells Transplanted on Platelet-Rich Fibrin Glue in the Treatment of Articular Cartilage Defects: A Pilot Study and Preliminary Results

Study Design Prospective case series, therapeutic Level IV. Objectives Functional and radiographic outcome evaluation of patients with spondylolysis treated with pars interarticularis defect repair with iliac bone grafting and application of a construct consisting of a pair of polyaxial pedicle screws connected by a U-shaped rod passing beneath the spinous process. Methods Twenty-five patients (27 operated lumbar levels) with an average of 20 months of follow-up (range 12-24 m) with spondylolysis who met our inclusion criteria were treated with the above-mentioned technique. Functional assessment was by the Visual Analog Score (VAS) for low back pain (LBP) and Oswestry Disability Index (ODI). Fusion was confirmed with plain x-rays and when indicated with computed tomography scan. Return to activities of daily living (ADL) was also assessed. Results There were 16 males (64%) and 9 females (36%), with a mean age of 18 ± 3 years at surgery, with a mean operating time of 79 ± 13 min and a mean blood loss of 186 ± 57 ml. ODI significantly improved from a mean of 63 ± 7 preoperatively to 10 ± 4 at 12 months postoperatively (P < 0.001). The mean preoperative LBP VAS score 8 ± 1 showed also a statistically significant decrease of values to 1 ± 1 at 12 months, (P < 0.001). At 12 m, all patients returned to unrestricted ADL. Pars healing was present in 19 patients (76%) at 6 months and in all patients at 12 months. Conclusions Polyaxial pedicular screws with a U-shaped rod offer an effective and reproducible treatment for spondylolysis with an appropriate fusion rate, predictable return to daily activities, and good pain relief in young adults.

Akram Azzam

Papers

The Clinical Use of Human Culture–Expanded Autologous Bone Marrow Mesenchymal Stem Cells Transplanted on Platelet-Rich Fibrin Glue in the Treatment of Articular Cartilage Defects: A Pilot Study and Preliminary Results

Repair of spondylolysis using a pedicle screw U-shaped rod construct: A preliminary study of 25 young patients with a mean follow-up of 24 months.