Elucidating pathological mechanisms of joint degenerative disorders

Joint degenerative disorders impose a large burden on lifestyle and the healthcare system. The goals of this thesis were to elucidate pathological mechanisms in osteoarthritis (OA) and juvenile osteochondritis dissecans (JOCD) in order to improve understanding of these diseases, and to provide well-characterized platforms for therapeutic development and testing. In order to bridge the gap in knowledge between preclinical and clinical studies, we characterized molecular events that occur in the rat medial meniscus transection model of post-traumatic OA as the disease develops and progresses. We then used this platform to investigate the mechanisms of action of micronized dehydrated human amnion/chorion membrane in order to elucidate potential disease-modifying mechanisms of this therapeutic. By utilizing cutting edge induced pluripotent stem cell technology, we established JOCD-specific models of chondrogenic and endochondral ossification differentiation, as well as endoplasmic reticulum-stress induction models. Our results shed light on pathological mechanisms of OA and JOCD and provided compelling data for the development of more targeted approaches for disease treatments.Ph.D

Understanding and leveraging cell metabolism to enhance mesenchymal stem cell transplantation survival in tissue engineering and regenerative medicine applications

International audienceIn 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. Significance statement: Lack of success of stem cell-based therapies has been largely attributed to the massive cell death observed post-transplantation, which is caused by the metabolic shock these cells experience as they transition from in vitro to a hostile, injured site in vivo. The metabolism in mesenchymal stem cells (MSCs), specifically, is highly sensitive to cellular and environmental cues. In order to improve cell survival rate posttransplantation, it is important that scientists understand, and take into account, the needs and demands of MSC metabolism as they design the next generation of MSC-based therapies

Stem cell-based approaches in cardiac tissue engineering: controlling the microenvironment for autologous cells

Cardiovascular disease is one of the leading causes of mortality worldwide. Cardiac tissue engineering strategies focusing on biomaterial scaffolds incorporating cells and growth factors are emerging as highly promising for cardiac repair and regeneration. The use of stem cells within cardiac microengineered tissue constructs present an inherent ability to differentiate into cell types of the human heart. Stem cells derived from various tissues including bone marrow, dental pulp, adipose tissue and umbilical cord can be used for this purpose. Approaches ranging from stem cell injections, stem cell spheroids, cell encapsulation in a suitable hydrogel, use of prefabricated scaffold and bioprinting technology are at the forefront in the field of cardiac tissue engineering. The stem cell microenvironment plays a key role in the maintenance of stemness and/or differentiation into cardiac specific lineages. This review provides a detailed overview of the recent advances in microengineering of autologous stem cell-based tissue engineering platforms for the repair of damaged cardiac tissue. A particular emphasis is given to the roles played by the extracellular matrix (ECM) in regulating the physiological response of stem cells within cardiac tissue engineering platforms