Carbonyl sulfide (COS) emissions in two agroecosystems in central France.

Carbonyl sulfide (COS) fluxes simulated by vegetation and soil component models, both implemented in the ORCHIDEE land surface model, were evaluated against field observations at two agroecosystems in central France. The dynamics of a biogenic process not yet accounted for by this model, i.e., COS emissions from croplands, was examined in the context of three independent and complementary approaches. First, during the growing seasons of 2019 and 2020, monthly variations in the nighttime ratio of vertical mole fraction gradients of COS and carbon dioxide measured between 5 and 180 m height (GradCOS/GradCO2), a proxy of the ratio of their respective nocturnal net fluxes, were monitored at a rural tall tower site near Orléans (i.e., a "profile vs. model" approach). Second, field observations of COS nocturnal fluxes, obtained by the Radon Tracer Method (RTM) at a sub-urban site near Paris, were used for that same purpose (i.e., a "RTM vs. model" approach of unaccounted biogenic emissions). This site has observations going back to 2014. Third, during the growing seasons of 2019, 2020 and 2021, horizontal mole fraction gradients of COS were calculated from downwind-upwind surveys of wheat and rapeseed crops as a proxy of their respective exchange rates at the plot scale (i.e., a "crop based" comparative approach). The "profile vs. model" approach suggests that the nocturnal net COS uptake gradually weakens during the peak growing season and recovers from August on. The "RTM vs. model" approach suggests that there exists a biogenic source of COS, the intensity of which culminates in late June early July. Our "crop based" comparative approach demonstrates that rapeseed crops shift from COS uptake to emission in early summer during the late stages of growth (ripening and senescence) while wheat crops uptake capacities lower markedly. Hence, rapeseed appears to be a much larger source of COS than wheat at the plot scale. Nevertheless, compared to current estimates of the largest COS sources (i.e., marine and anthropogenic emissions), agricultural emissions during the late stages of growth are of secondary importance.

Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases.

BACKGROUND: Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) revealed their key role in immune regulation, offering promising therapeutic perspectives for immune and inflammatory diseases. We aimed to develop a production process of an UC-MSC-based product and then to characterize UC-MSC properties and immunomodulatory activities in vitro, related to their clinical use and finally, to transfer this technology to a good manufacturing practice (GMP) compliant facility, to manufacture an advanced therapy medicinal product (ATMP). METHODS: Fifteen human umbilical cords (UCs) were collected to develop the production process. Three batches of UC-MSCs from a single donor were characterized at basal state and after in vitro pro-inflammatory stimulation by interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα). Proliferation, immunophenotype, activation markers' expression and the inhibition of T cell proliferation were assessed. Finally, this technology was transferred to a GMP-compliant facility to manufacture an UC-MSC-based ATMP, from a single donor, using the explant method followed by the establishment of master and work cell stocks. RESULTS: Twelve UCs were processed successfully allowing to isolate UC-MSCs with doubling time and population doubling remaining stable until passage 4. CD90, CD105, CD73, CD44, CD29, CD166 expression was positive; CD14, CD45, CD31, HLA-DR, CD40, CD80 and CD86 expression was negative, while CD146 and HLA-ABC expression was heterogeneous. Cell morphology, proliferation and immunophenotype were not modified by inflammatory treatment. Indoleamine 2,3-dioxygenase (IDO) expression was significantly induced by IFNγ and IFNγ + TNFα versus non-treated cells. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression was induced significantly after priming. T cell proliferation was significantly decreased in the presence of UC-MSCs in a dose-dependent manner. This inhibitory effect was improved by IFNγ or IFNγ + TNFα, at UC-MSCs:PBMC ratio 1:10 and 1:30, whereas only IFNγ allowed to decrease significantly T cell proliferation at ratio 1:100. The manufacturing process of the UC-MSC-based ATMP was qualified and authorized by the French regulatory agency for clinical use (NCT04333368). CONCLUSION: This work allowed to develop an investigational UC-MSC-based ATMP authorized for clinical use. Our results showed that an inflammatory environment preserves the biological properties of UC-MSCs with an improvement of their immunomodulatory functions.

Human umbilical cord-derived mesenchymal stem/stromal cells: a promising candidate for the development of advanced therapy medicinal products.

Umbilical cord-derived mesenchymal stem/stromal cells (UC-MSCs) emerge as a perspective for therapeutic use in immune and inflammatory diseases. Indeed, immunomodulatory and anti-inflammatory properties, associated to fewer ethical, availability, and safety issues, position UC-MSCs as a promising active substance to develop medicinal products. Since 2007, UC-MSC-based products are classified as advanced therapy medicinal products (ATMP) according to the European Regulation 1394/2007/EC. This new regulatory status required a total adaptation of stakeholders wishing to develop UC-MSC-based ATMPs. Cell production in tissue and cell banks has been replaced by the manufacturing of a medicine, in authorized establishments, according to the good manufacturing practices (GMP) specific to ATMPs. After a brief description of UC-MSCs, we described in this review their recent use in a large panel of immune and inflammatory pathologies, including early and late phase clinical trials. Despite the use of the same product, we noticed an important heterogeneity in terms of indication, posology and study design. Then, we discussed regulatory and manufacturing challenges for stakeholders, especially in terms of process harmonization and cells characterization. Our aim was to point that despite MSCs use for several decades, the development of an UC-MSC-based ATMP remains at this day a real challenge for both academic institutions and pharmaceutical companies.