Role of mesenchymal stem cells in osteoarthritis therapy

Osteoarthritis (OA) is the most common joint disease encountered worldwide. OA of the knees is particularly common, with radiographic OA of the tibiofemoral compartment occurring in 5-15% of people aged 35-74 years. Currently, adult stem cells are being evaluated for various therapeutic approaches, including OA. However, the efficacy of mesenchymal stem cells (MSC) in the treatment of OA is controversial.
Recently, major advances in the development of animal models for cell therapy and cell-based gene therapy have been accomplished in my laboratory. To further explore the therapeutic potential of regenerative treatment protocols, it is necessary to trace the fate of individual donor or manipulated cells in the host organism. However, immune-mediated rejection of labeled cells is a general problem in transplantation studies using cells labeled with any immunogenic marker, and also in gene therapy protocols.
In proof-of-principle experiments, we were able to establish a syngeneic rat model for long-term histological cell tracking in the absence of immune-mediated rejection of labeled cells in immunocompetent animals by inducing specific tolerance to the marker gene through neonatal tolerization.
In addition, we found that the genetic marker human placental alkaline phosphatase (ALPP) provides superb detection quality in hard tissues, because this heat stable marker enzyme survives not only paraffin but also methylmethacrylate embedding. Recently, we generated a novel in vivo cell tracking system consisting of a transgenic donor and a corresponding marker tolerant transgenic recipient mouse line on the same inbred background.
The donor line ubiquitously expresses wild type ALPP, whereas the recipient line expresses a mutated form of the marker (ALPPE451G) which can be easily distinguished from the wild-type form by its heat sensitivity.
Because only a single amino acid is different between wild-type and mutated ALPP, ALPPE451G-transgenic mice are tolerant to ALPP. The patents for these inventions are pending. In the proposed project we intend to 1) generate a ALPP/ALPPE451G transgenic marker tolerant rat model, using the same technology that we established for mice, and to employ this model to study 2) the factors governing the attachment of intra-articularly injected MSC to damaged cartilage, and 3) the long-term survival and efficacy of intra-articularly injected MSC in OA rats, as well as the migration of intra-articularly injected MSC to other organs. In ALPPE451G marker tolerant recipients, OA of the knee will be induced by destabilization of the medial meniscus. MSC isolated and expanded from syngeneic ALPP transgenic rats will be used as genetically labeled cells.
We are positive that the proposed project will significantly increase our understanding of the behavior, efficacy and safety of autologous MSC in OA therapy. Therefore, this project may have important implications for clinical medicine.

Related Papers (Titel+Pubmed-Link):

Marker-tolerant, immunocompetent animals as a new tool for regenerative medicine and long-term cell tracking.
Odörfer K.I., Unger N.J., Weber K., Sandgren E.P., Erben R.G.
BMC Biotechnol. 2007 Jun 8;7:30 1

Human placental alkaline phosphatase as a tracking marker for bone marrow mesenchymal stem ells
Balmayor E.R., Flicker M., Käser T., Saalmüller A., Erben R.G.
Biores Open Acess 2013 Oct;2(5):346-55 2



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