Mesenchymal stromal cells: 2001-2018 current situation of this therapeutic innovation in animal healthcare and industry point of view

La médecine régénérative vétérinaire a fait d’énormes progrès en 20 ans. Le mécanisme d’action des cellules stromales mésenchymateuses (CSM) a été complètement révisé ; les CSM sont passées du statut de cellules qui se différencient localement pour reformer un nouveau tissu persistant, à celui de cellules signalisatrices médicinales qui interagissent transitoirement avec le micro-environnement pour rétablir les conditions propices à une cicatrisation tissulaire efficace. De fait, l’utilisation des CSM qui a été longtemps restreinte à une approche autologue et principalement pour des applications orthopédiques, s’est élargie à l’approche allogénique vers d’autres affections inflammatoires ou dysimmunitaires de médecine interne. Cependant, la multitude des sources de CSM et des procédés de production rendent les études difficilement comparables entre elles. Le vétérinaire a aujourd’hui accès à un large choix de produits cellulaires mais ne dispose que des informations commerciales ou de la littérature scientifique spécialisée pour faire un choix. Cette revue fait l’état des lieux des connaissances actuelles sur le sujet en médecine vétérinaire et humaine.Great strides have been in made in the last two decades in the field of veterinary regenerative medi¬cine. Mesenchymal Stromal Cells’ (MSCs) mechanism of action has been completely revisited. MSCs, wishfully thought as cells being able to differenciate themselves and replace damaged tissue, have turned out to be only transient but key signalling cells, interacting with the microenvironment to restore the conditions for an efficient tissue healing process. This new perceiption of their mechanims of action has drived the expansion of their use, initially restricted to autologous treatments of ortho¬paedic conditions, to allogenic treatments to tackle diverse inflammatory and immune problems. However, both the diversity of the sources of MSCs and the use of different production processes, can render scientific data analysis confusing ; especially for veterinarians who now have at their fingertips a choice of an wide array of therapeutic cellular products. In this review we aim to clarify the current state of the art in animal regenerative medicine, while lightening them with scientific data from studies in man

Long-Term Safety and Efficacy of Single or Repeated Intra-Articular Injection of Allogeneic Neonatal Mesenchymal Stromal Cells for Managing Pain and Lameness in Moderate to Severe Canine Osteoarthritis Without Anti-inflammatory Pharmacological Support: Pilot Clinical Study

Objective: To explore the long-term safety and efficacy of canine allogeneic mesenchymal stromal cells (MSC) administered intra-articularly as single or repeated injections in appendicular joints of dogs affected by moderate to severe refractory osteoarthritis.Study Design: 22 pet dogs were recruited into a non-randomized, open and monocentric study initially administering one cellular injection. A second injection was offered after 6 months to owners if the first injection did not produce expected results.Materials and Methods: Anti-inflammatory treatment (if prescribed) was discontinued at last one week before the onset of treatment. Each injection consisted of at least 10 million viable neonatal allogeneic mesenchymal stromal cells obtained from fetal adnexa. Medical data was collected from veterinary clinical evaluations of joints up to 6 months post-injection and owner's assessment of their dog's mobility and well-being followed for a further 2 years when possible.Results: Mild, immediate self-limiting inflammatory joint reactions were observed in 5/22 joints after the first injection, and in almost all dogs having a subsequent injection. No other MSC-related adverse medical events were reported, neither during the 6 months follow up visits, nor during the long-term (2-years) safety follow up. Veterinary clinical evaluation showed a significant and durable clinical improvement (up to 6 months) following MSC administration. Eight dogs (11 joints) were re-injected 6 months apart, sustaining clinical benefits up to 1 year. Owner's global satisfaction reached 75% at 2 years post-treatmentConclusion: Our data suggest that a single or repeated intra-articular administration of neonatal MSC in dogs with moderate to severe OA is a safe procedure and confer clinical benefits over a 24-month period. When humoral response against MSC is investigated by flow cytometry, a positive mild and transient signal was detected in only one dog from the studied cohort, this dog having had a positive clinical outcome

Le couple C-KIT/SCF dans l'hématopoïese (revue de la littérature)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocTOULOUSE3-BU Santé-Allées (315552109) / SudocSudocFranceF

Modulation du métabolisme du céramide dans la réponse des cellules leucémiques aux rayonnements ionisants

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Differences in the intrinsic chondrogenic potential of equine umbilical cord matrix and cord blood mesenchymal stromal/stem cells for cartilage regeneration

International audienceUmbilical cord blood mesenchymal stromal/stem cells (UCB-MSCs) and umbilical cord matrix MSCs (UCM-MSCs) have chondrogenic potential and are alternative sources to standard surgically derived bone marrow or adipose tissue collection for cartilage engineering. However, the majority of comparative studies explore neonatal MSCs potential only on ISCT benchmark assays accounting for some bias in the reproducibility between in vitro and in clinical studies. Therefore, we characterized equine UCB-MSCs and UCM-MSCs and investigated with particular attention their chondrogenesis potential in 3D culture with BMP-2 + TGF-ß1 in normoxia or hypoxia. We carried out an exhaustive characterization of the extracellular matrix generated by both these two types of MSCs after the induction of chondrogenesis through evaluation of hyaline cartilage, hypertrophic and osteogenic markers (mRNA, protein and histology levels). Some differences in hypoxia sensitivity and chondrogenesis were observed. UCB-MSCs differentiated into chondrocytes express an abundant, dense and a hyaline-like cartilage matrix. By contrast, despite their expression of cartilage markers, UCM-MSCs failed to express a relevant cartilage matrix after chondrogenic induction. Both MSCs types also displayed intrinsic differences at their undifferentiated basal status, UCB-MSCs expressing higher levels of chondrogenic markers whereas UCM-MSCs synthesizing higher amounts of osteogenic markers. Our results suggest that UCB-MSCs should be preferred for ex-vivo horse cartilage engineering. How those results should be translated to in vivo direct cartilage regeneration remains to be determined through dedicated study

Publisher Correction: Differences in the intrinsic chondrogenic potential of equine umbilical cord matrix and cord blood mesenchymal stromal/stem cells for cartilage regeneration

International audienceAn amendment to this paper has been published and can be accessed via a link at the top of the paper

Human cord blood-derived hematopoietic and neural-like stem/progenitor cells are attracted by the neurotransmitter GABA.

International audienceMigration of stem/progenitor cells is a crucial event for homing toward tissue where cells need to be renewed. The neurotransmitter gamma-aminobutyric acid (GABA) has been shown to have a crucial role in migration of neuronal stem/progenitor cells. Since human umbilical cord blood (HUCB) contains stem/progenitor cells able to generate either neuronal or hematopoietic cells, we evaluated the effect of GABA on this type of cells. While whole fraction of mononuclear cells expressed GABA(A) and GABA(B) receptor subunits (GABA-R), only GABA(B)R subunits were found to be expressed on immature CD133+ cells. Functional experiments revealed that both cell fractions of HUCB were attracted by a gradient of GABA concentration and furthermore were blocked by specific antagonists of GABA(A)R and GABA(B)R bicuculline and saclofen, respectively. Moreover, through GABA(B)R activation the migrating fraction was highly enriched by both hematopoietic progenitors and cells able to generate neuron- like cells in culture. Therefore, GABA is a potent chemoattractant of HUCB stem/progenitor cells specifically through GABA(B)R activation

Biosafety Evaluation of Equine Umbilical Cord-Derived Mesenchymal Stromal Cells (UC-MSCs) by Systematic Pathogen Screening in Peripheral Maternal Blood and Paired UC-MSCs

International audienc

Evaluation of biosafety of equine amniotic membranes for allogeneic use – a pilot study using PCR pathogens screening on peripheric maternal blood and paired fetal adnexa

International audienceTransplantation of amniotic membranes (AM) is increasingly used for equine tissue reconstruction. However, there is currently no published data on systematic screening of donor mares for infectious diseases, in contrast to human medicine. To minimize the risk of iatrogenic donor‐borne contamination, we questioned the biosafety of equine AM. We hypothesized that the processed amnion layer of AM is less exposed than peripheric maternal blood (PMB) to pathogens, aiming to assess the risk of vertical contamination of AM from mares potentially carrying common equine infectious agents. The study was conducted on 6 fetal membrane collections during foaling seasons 2016–2017. Systematic Coggins test and PCR screening for B. caballi, T. equi, A. phagocytophilum, B. burgdorferi, Leptospira spp, Mycoplasma spp, R. equi, equine arteritis virus, equine herpesviruses type 1, 2, 4 and 5 were performed on PMB. The amnion layer was isolated, processed and frozen down at −80°C. Mycoplasma PCR screening and bacteriological and fungal cultures were performed to exclude environmental contamination. In case of one or more positive PCR result(s) on PMB, a PCR analysis for the detected pathogen(s) was conducted on a biopsy sample of the associated AM. All PMB samples were PCR positive for at least one pathogen: 3 for EHV2, 3 for EHV2 and EHV5. All AM samples were negative for these specific pathogens. In conclusion of this pilot study, processed equine AM appear free of donor‐borne contamination, even for vertically communicable pathogens such as gammaherpesviruses. More data is needed to assess the residual risk of contamination of amnion tissue when the mare is positive for one or more infectious agent(s). Also, emerging pathogens like hepaciviruses should be included in the future

Evaluation of biosafety of equine amniotic membranes for allogeneic use – a pilot study using PCR pathogens screening on peripheric maternal blood and paired fetal adnexa.

International audienc