ATYPiCAL

The development of tissue engineering (TE) now allows considering the clinical use for osteoarticular defects of Mesenchymal Stem Cells (MSC) for preparing biocartilage. Thanks to their capacity of proliferation and differentiation, MSC appear to be currently one of the most promising ways of obtaining cartilage cells. The conjunctive tissue of the umbilical cord or Wharton’s jelly (WJ) is an abundant and promising source of MSC for clinical applications. They present immunomodulatory properties and have a higher proliferation potential than MSC from adult tissues. All these advantages enable this source to represent a virtually inexhaustible source of stem cells especially for allogeneic TE therapies. However, immunomodulatory properties of WJ-MSC must be precisely defined as they will be used in an allogeneic clinical context as an Advanced Therapy Medicinal Product (ATMP) according to the European regulation (1394/2007). The ATYPiCAL project, which comprises 4 complementary teams and a spin off, is the subject of funding project with the agency ANR-PRCE 2015. The innovative proposed strategy relies on a stratified scaffold and consists in using MSC from Wharton’s Jelly (WJ-MSC), extemporaneously embedded into an Alginate/Hyaluronic Acid (Alg/HA) layer guiding cells to chondrogenic differentiation then associated to the NanoM1 medical device (ARTiOS NanoMed) inducing subchondral bone regeneration. An important concern is the use of allogeneic MSC in tissue engineering. The originalities of this present project are: (i) To perform a technological transfer from research laboratories (UMR 7365 and “Laboratoire d’Immunologie de la Transplantation” of CEA) towards the hospital (UTCT). The transfer consists in adjusting MSC isolation, production and conservation methods developed by UMR 7365 lab in clinical grade conditions at the UTCT. The MSC amplification will be done until the 1st passage and will be followed by a quality control developed by the UMR 7365 and “Laboratoire d’Immunologie de la Transplantation” (CEA) (self-renewal and phenotype stability, genetic stability and cell ageing, differentiation potential, immunomodulation properties). In order to produce clinical grade WJ-MSC in compliance with the current French regulations in the area of Advanced Therapy Medicinal Product (ATMP), the cell culture will take place in a culture medium enriched by human platelet growth factors in order to be free from the presence of animal proteins. (ii) To use an innovative stratified scaffold and to investigate the construction impact onto chondrogenic differentiation in vitro and in vivo. (iii) To characterize the immunomodulatory properties of WJ-MSC during chondrogenic differentiation in both in vitro and in vivo studies with functional tests at each step. (iv) To check, in vitro, that immune response currently observed in an allogeneic context does not negatively interfere with chondrogenic differentiation. The expected results should allow assessing the feasibility and validating the clinical grade amplification technique as well as obtaining precisely characterized and secured MSC. This project will eventually diversify the ATMP field in France implementing an essential skill to therapeutic progress.