In tissue engineering and regenerative medicine, stem cell-specifically, mesenchymal stromal/stem cells (MSCs)-therapies have fallen short of their initial promise and hype. The observed marginal, to no benefit, success in several applications has been attributed primarily to poor cell survival and engraftment at transplantation sites. MSCs have a metabolism that is flexible enough to enable them to fulfill their various cellular functions and remarkably sensitive to different cellular and environmental cues. At the transplantation sites, MSCs experience hostile environments devoid or, at the very least, severely depleted of oxygen and nutrients. The impact of this particular setting on MSC metabolism ultimately affects their survival and function. In order to develop the next generation of cell-delivery materials and methods, scientists must have a better understanding of the metabolic switches MSCs experience upon transplantation. By designing treatment strategies with cell metabolism in mind, scientists may improve survival and the overall therapeutic potential of MSCs. Here, we provide a comprehensive review of plausible metabolic switches in response to implantation and of the various strategies currently used to leverage MSC metabolism to improve stem cell-based therapeutics.
s u m m a r yObjective: To characterize local disease progression of the medial meniscus transection (MMT) model of post-traumatic osteoarthritis (OA) at the molecular level, in order to establish a baseline for therapeutic testing at the preclinical stage. Design: Weight-matched male Lewis rats underwent MMT or sham surgery on the left limb with the right leg as contralateral control. At 1 and 3 weeks post-surgery, tissues were harvested from different areas of the articular cartilage (medial and lateral tibial plateaus, and medial osteophyte region) and synovium (medial and lateral), and analyzed separately. RNA was extracted and used for microarray (RT-PCR) analysis. Results: Gene expression changes due to surgery were isolated to the medial side of the joint. Gene changes in chondrocyte phenotype of the medial tibial plateau cartilage preceded changes in tissue composition genes. Differences in inflammatory markers were only observed at the osteophyte region at 3 weeks post-surgery. There was surgical noise in the synovium at week 1, which dissipated at week 3. At this later timepoint, meniscal instability resulted in elevated expression of matrix degradation proteins and osteogenic markers in the synovium and cartilage. Conclusion: These results suggest feedback interactions between joint tissues during disease progression. Regional tissue expression differences found in MMT joints indicated similar pathophysiology to human OA, and provided novel insights about this degeneration model. The examination of gene expression at a localized level in multiple tissues provides a well-characterized baseline to evaluate mechanistic effects of potential therapeutic agents on OA disease progression in the MMT model.
Osteoarthritis (OA) is a widespread disease that continues to lack approved and efficacious treatments that modify disease progression. Micronized dehydrated human amnion/chorion membrane (m-dHACM) has been shown to be effective in reducing OA progression, but many of the engineering design parameters have not been explored. The objectives of this study were to characterize the particle size distributions of two m-dHACM formulations and to investigate the influence of these distributions on the in vivo therapeutic efficacy of m-dHACM. Male Lewis rats underwent medial meniscus transection (MMT) or sham surgery, and intra-articular injections of saline, m-dHACM, or reduced particle size m-dHACM (RPS m-dHACM) were administered at 24 hours postsurgery (n = 9 per treatment group). After 3 weeks, the animals were euthanized, and left legs harvested for equilibrium partitioning of an ionic contrast agent microcomputed tomography and histological analysis. m-dHACM and RPS m-dHACM particles were fluorescently tagged and particle clearance was tracked in vivo for up to 42 days postsurgery. Protein elution from both formulations was quantified in vitro. Treatment with m-HACM, but not RPS m-dHACM, reduced lesion volume in the MMT model 3 weeks postsurgery. In contrast, RPS m-dHACM increased cartilage surface roughness and osteophyte cartilage thickness and volume compared to saline treatment. There was no difference of in vivo fluorescently tagged particle clearance between the two m-dHACM sizes. RPS m-dHACM showed significantly greater protein elution in vitro over 21 days. Overall, delivery of RPS m-dHACM did result in an increase of in vivo joint degeneration and in vitro protein elution compared to m-dHACM, but did not result in differences in joint clearance in vivo. These results suggest that particle size and factor elution may be tailorable factors that are important to optimize for particulate amniotic membrane treatment to be an effective therapy for OA.
Characterization of articular cartilage morphology and composition using microcomputed tomography (microCT) techniques requires the use of contrast agents to enhance X-ray attenuation of the tissue. This chapter describes the use of an anionic iodinated contrast agent at equilibrium with articular cartilage. In this technique, negatively charged contrast agent molecules distribute themselves inversely with respect to the negatively charged proteoglycans (PGs) within the cartilage tissue (Palmer et al. Proc Natl Acad Sci U S A 103:19255-19260, 2006). This relationship allows for assessment of cartilage degradation, as areas of high X-ray attenuation have been shown to correspond to areas of depleted PGs (Palmer et al. Proc Natl Acad Sci U S A 103:19255-19260, 2006; Xie et al. Osteoarthritis Cartilage 18:65-72, 2010).
Disease-specific pluripotent stem cells can be derived through genetic manipulation of embryonic stem cells or by reprogramming somatic cells (induced pluripotent stem cells).
Repair and reconstruction of large bone defects remain a significant challenge. Cell construct, containing mesenchymal stem cells (MSCs) and scaffold, is a promising strategy for addressing and treating major orthopedic clinical conditions. However, the design of an ideal cell construct for engineering bone faces two critical challenges (i) matching the scaffold degradation rate to that of new bone formation and (ii) preventing the massive cell death post-implantation (caused by disruption of oxygen and nutrient supply). We will hereby primarily focus on the challenge of survival of MSCs post-implantation. Increasing evidence indicates that metabolic regulation plays a critical role in cell fate and functions. In cell metabolism, glucose is considered the major metabolic substrate to produce ATP via glycolysis when the availability of oxygen is limited. In this paper, we delineate the essential roles of glucose on MSC survival. We aim to provide a different perspective which highlights the importance of considering glucose in the development of tissue engineering strategies in order to improve the efficiency of MSC-based cell constructs in the repair of large bone defects.
Mesenchymal stromal cells (MSCs) are considered promising candidates for regenerative medicine applications. Their clinical performance post-implantation, however, has been disappointing. This lack of therapeutic efficacy is most likely due to suboptimal formulations of MSC-containing material constructs. Tissue engineers, therefore, have developed strategies addressing/incorporating optimized cell-, microenvironmental-, biochemical, -and biophysical-cues/stimuli to enhance MSCcontaining construct performance. Such approaches have had limited success because they overlooked that maintenance of MSC viability after implantation for a sufficient time is necessary for MSCs to develop their regenerative functionalities fully. Following a brief overview of glucose metabolism and regulation in MSCs, the present literature review includes recent pertinent findings that challenge old paradigms and notions. We hereby report that glucose is the primary energy substrate for MSCs, provides precursors for biomass generation, and regulates MSC functions, including proliferation and immunosuppressive properties. More importantly, glucose metabolism is central in controlling in vitro MSC expansion, in vivo MSC viability, and MSC-mediated angiogenesis post-implantation when addressing MSC-based therapies. Meanwhile, in silico models are highlighted for predicting glucose needs of MSCs in specific regenerative medicine settings, which will eventually enable tissue engineers to design viable and potent tissue constructs. This new knowledge should be incorporated into developing novel effective MSC-based therapies.
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