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Advanced therapy medicinal products (ATMPs) represent a new class of biological medicines. The European regulation has classified ATMPs into three categories: gene therapy medicinal products, somatic cell therapy medicinal products, and Tissue-Engineered products. If one of these categories incorporates a medical device, the medicine is defined as a Combined ATMP. The specificity and complexity of these innovative drugs have required a complete reorganization of hospital and pharmaceutical circuits, from patient eligibility to drug administration. Indeed, increased interaction and collaboration between different healthcare professionals are essential in order to guarantee quality and safety of these innovative medicines.

Summary Purpose of the study The purpose of our study was to investigate the effects of ovine umbilical cord-derived mesenchymal stromal cells (UC-MSCs) seeded in a fibrin patch as an adjuvant therapy for fetal myelomeningocele repair in the ovine model. Materials and methods MMC defects were surgically created at 75 days of gestation and repaired 15 days later with UC-MSCs patch or an acellular patch. At birth, motor function, tail movements, and voiding abilities were recorded. Histological and immunohistochemical analysis included study of MMC defect's healing, spinal cord, UC-MSCs survival, and screening for tumors. Results Six lambs were born alive in each group. There was no difference between the two groups on the median sheep locomotor rating score but all lambs in the control group had a score between lower than 3 compared to 50% in UC-MSCs group. There were more lambs with tail movements and voiding ability in UC-MSCs group (83% vs 0% and 50% vs 0%, respectively). gray matter area and large neurons density were higher in UC-MSCs group (2.5 vs 0.8 mm2 and 19.3 vs 1.6 neurons/mm2 of gray matter, respectively). Fibrosis thickness at the myelomeningocele scar level was reduced in UC-MSCs group (1269 µm vs 2624 µm). No tumors were observed. Conclusion Fetal repair of myelomeningocele using allogenic UC-MSCs patch provides a moderate improvement in neurological functions, gray matter and neuronal preservation and prevented from fibrosis development at the myelomeningocele scar level.

In order to induce an efficient bone formation with human bone marrow mesenchymal stromal cells (hBMSC) associated to a scaffold, it is crucial to determine the key points of the hBMSC action after in vivo transplantation as well as the appropriate features of a scaffold. To this aim we compared the hBMSC behavior when grafted onto two biomaterials allowing different bone potential in vivo. The cancellous devitalized Tutoplast®-processed bone (TPB) and the synthetic hydroxyapatite/β-tricalcium-phosphate (HA/βTCP) which give at 6weeks 100% and 50% of bone formation respectively. We first showed that hBMSC adhesion is two times favored on TPB in vitro and in vivo compared to HA/βTCP. Biomaterial structure analysis indicated that the better cell adhesion on TPB is associated to its higher and smooth open pore architecture as well as its content in collagen. Our 6week time course analysis, showed using qPCR that only adherent cells are able to survive in vivo giving thus an advantage in term of cell number on TPB during the first 4weeks after graft. We then showed that grafted hBMSC survival is crucial as cells participate directly to bone formation and play a paracrine action via the secretion of hIGF1 and hRANKL which are known to regulate the bone formation and resorption pathways respectively. Altogether our results point out the importance of developing a smooth and open pore scaffold to optimize hBMSC adhesion and ensure cell survival in vivo as it is a prerequisite to potentiate their direct and paracrine functions.Around 10% of skeletal fractures do not heal correctly causing nonunion. An approach involving mesenchymal stromal cells (MSC) associated with biomaterials emerges as an innovative strategy for bone repair. The diversity of scaffolds is a source of heterogeneity for bone formation efficiency. In order to better determine the characteristics of a powerful scaffold it is crucial to understand their relationship with cells after graft. Our results highlight that a biomaterial architecture similar to cancellous bone is important to promote MSC adhesion and ensure cell survival in vivo. Additionally, we demonstrated that the grafted MSC play a direct role coupled to a paracrine effect to enhance bone formation and that both of those roles are governed by the used scaffold.

Le sepsis est une infection associee a un syndrome de reponse inflammatoire systemique conduisant a des dommages tissulaires et des defaillances d’organes pouvant entrainer une mort rapide [1] . L’une des consequences du sepsis peut etre l’atrophie musculaire, pouvant avoir de nombreux impacts cliniques [1] . En situation normale, le muscle squelettique a la capacite de regenerer ad-integrum apres une blessure, grâce aux cellules souches : les cellules satellites [2] . Nous avons montre qu’apres un choc septique, les cellules souches musculaires ne sont plus capables d’assurer de nombreuses fonctions comme leur activation, la division ou la differentiation. Ces effets perdurent dans le temps et l’effet negatif du sepsis a l’echelle cellulaire se fait ressentir meme 3 mois apres le choc septique. Nous avons egalement montre que ces defauts proviennent, en partie des mitochondries, dont la masse s’effondre et l’activite augmente entrainant une deterioration de l’etat metabolique. L’injection de cellules souches mesenchymateuses s’est egalement revelee interessante pour contrer ces dysfonctions, entrainant une diminution systemique de l’inflammation et une restauration quasi complete de tous les parametres des cellules souches musculaires. Cette injection de cellules souches mesenchymateuses entraine egalement une amelioration fonctionnelle du muscle avec un reel gain de force a l’echelle de la fibre, contrant ainsi la perte de masse musculaire et de la force engendree par le sepsis.

Le sepsis est une infection qui resulte en une inflammation non controlee conduisant a des dommages tissulaires et des defaillances d’organes multiples, pouvant entrainer une mort rapide. De nos jours, les traitements ne sont pas tres efficaces [1] , [2] et l’une des consequences du sepsis peut etre la perte de masse musculaire, entrainant une atrophie pouvant avoir de nombreux impacts cliniques [3] . En situation normale le muscle squelettique a la capacite de regenerer ad integrum apres une blessure, grâce aux cellules souches du muscle : les cellules satellites [3] , [4] , [5] , [6] , [7] . Ayant un role central dans la regeneration, notre travail consiste a caracteriser le comportement de cette cellule souche au cours d’un sepsis afin de comprendre pourquoi, meme 5 ans apres un choc septique ce type cellulaire n’est plus capable de remplir son role dans le maintien de l’homeostasie musculaire et de corriger le probleme. Nous avons montre qu’apres un choc septique, les cellules souches musculaires ne sont plus capables d’assurer de nombreuses fonctions lors de leur activation comme la division et la differentiation. Ces effets perdurent dans le temps et l’effet negatif du sepsis a l’echelle cellulaire se fait ressentir meme 3 mois apres le choc septique. Nous avons egalement montre que ces defauts proviennent, en partie des mitochondries, entrainant une deterioration de l’etat metabolique. L’injection de cellules souches mesenchymateuses s’est egalement revelee interessante pour contrer ces dysfonctions, montrant une diminution systemique de l’inflammation et une restauration quasi complete de tous les parametres des cellules souches musculaires.