Contribution of fetal microchimeric cells to maternal wound healing in sickle cell ulcers

Leg ulcers are a major complication of sickle cell disease (SCD). They are particularly challenging to treat and innovative therapies are needed. We previously showed that the healing of SCD ulcers is delayed because of decreased angiogenesis. During pregnancy, fetal microchimeric cells (FMC) transferred to the mother are recruited to maternal wounds and improve angiogenesis. After delivery, FMC persist in maternal bone marrow for decades. Here, we investigated whether fetal cells could also improve SCD ulcers in the post-partum setting. We found that skin healing was similarly improved in post-partum mice and in pregnant mice, through increased proliferation and angiogenesis. In a SCD mouse model that recapitulates refractory SCD ulcers, we showed that the ulcers of post-partum SCD mice healed more quickly than those of virgin mice. This was associated with the recruitment of fetal cells in maternal wounds where they harbored markers of leukocytes and endothelial cells. In a retrospective cohort of SCD patients, using several parameters we found that SCD women who had ever had a baby had less of a burden related to leg ulcers compared to nulliparous women. Taken together, these results indicate that healing capacities of FMC are maintained long after delivery and may be exploited to promote wound healing in post-partum SCD patients

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Epidermal development and homeostasis

SCOPUS: ed.jinfo:eu-repo/semantics/publishe

Cicatrisation cutanée normale et pathologique (analyse du rôle des cellules souches extra-cutanées et de certains mécanismes moléculaires)

La cicatrisation cutanée est un processus dans lequel des progéniteurs hématopoïétiques et endothéliaux sont recrutés dans les plaies à partir du sang et de la moelle osseuse. Au cours de la grossesse, des progéniteurs sont transférés de l enfant chez la mère et persistent plusieurs années après l accouchement dans des niches. Nous avons d abord étudié l implication de cellules fœtales au cours de la cicatrisation cutanée maternelle chez des souris sauvages (WT) gestantes de fœtus transgéniques GFP. Les cellules fœtales ont été détectées dans toutes les plaies maternelles non cicatrisées mais disparaissaient après cicatrisation complète. Le phénotype des cellules fœtales dans les plaies variait selon les phases de la cicatrisation : inflammatoire dans les phases précoces et endothélial dans les phases tardives. Des vaisseaux constitués entièrement de cellules endothéliales fœtales étaient retrouvés dans les plaies maternelles démontrant le transfert de progéniteurs endothéliaux fœtaux. La cicatrisation mobilisait des cellules fœtales CD34+ckit- mais qui n avaient pas le phénotype classique des progéniteurs endothéliaux circulants CD34+CD11b-VEGFR2+. Dans la deuxième partie, nous nous somme intéressés au rôle des calpaïnes protéases impliquées dans la motilité cellulaires dans la cicatrisation cutanée. Chez des souris transgéniques surexprimant la calpastatine, inhibiteur physiologique des calpaïnes, la cicatrisation était retardée comparée aux WT, avec diminution de la prolifération cellulaire, de l infiltrat inflammatoire et de la surface vasculaire sanguine. Dans les phases tardives, les calpaïnes participent au dépôt de collagène dans la cicatricePARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Dichotomization of primary outcomes serves external validity

International audienceno abstrac

Cancer Stem Cells: Basic Concepts and Therapeutic Implications

Different mechanisms contribute to intratumor heterogeneity, including genetic mutations, the microenvironment, and the existence of subpopulations of cancer cells with increased renewal capacity and the ability to recapitulate the heterogeneity found in primary tumors, which are referred to as cancer stem cells (CSCs). In this review, we discuss how the concept of CSCs has been defined, what assays are currently used to define the functional properties of CSCs, what intrinsic and extrinsic mechanisms regulate CSC functions, how plastic CSCs are, and the importance of epithelial-to-mesenchymal transition in conferring CSC properties. Finally, we discuss the mechanisms by which CSCs may resist medical therapy and contribute to tumor relapse.SCOPUS: ar.kinfo:eu-repo/semantics/publishe

Fetal microchimerism in skin wound healing

Skin wound healing is a complex regenerative process involving various cell types. We recently investigated whether fetal microchimeric cells (FMCs) acquired during gestation contribute to maternal wound healing and used fetal microchimerism to investigate the recruitment of distant endothelial progenitor cells in skin wounds. Our study showed that fetal progenitor cells are recruited into maternal wounds and participate in inflammation and angiogenesis. These fetal cells might have beneficial effects in situations of maternal defective healing, and might also modify the adult maternal wound environment toward a scarless fetal-like wound healing

Calpain activity is essential in skin wound healing and contributes to scar formation

Wound healing is a multistep phenomenon that relies on complex interactions between various cell types. Calpains are ubiquitously expressed proteases regulating several processes including cellular adhesion and motility as well as inflammation and angiogenesis. Calpains can be targeted by inhibitors, and their inhibition was shown to reduce organ damage in various disease models. We aimed to assess the role of calpains in skin healing and the potential benefit of calpain inhibition on scar formation. We used a pertinent model where calpain activity is inhibited only in lesional organs, namely transgenic mice overexpressing calpastatin (CPST), a specific natural calpain inhibitor. CPST mice showed a striking delay in wound healing particularly in the initial steps compared to wild types (WT). CPST wounds displayed reduced proliferation in the epidermis and delayed re-epithelization. Granulation tissue formation was impaired in CPST mice, with a reduction in CD45+ leukocyte infiltrate and in CD31+ blood vessel density. Interestingly, wounds on WT skin grafted on CPST mice (WT/CPST) showed a similar delayed healing with reduced angiogenesis and inflammation compared to wounds on WT/WT mice demonstrating the implication of calpain activity in distant extra-cutaneous cells during wound healing. CPST wounds showed a reduction in alpha-smooth muscle actin (alpha SMA) expressing myofibroblasts as well as alpha SMA RNA expression suggesting a defect in granulation tissue contraction. At later stages of skin healing, calpain inhibition proved beneficial by reducing collagen production and wound fibrosis. In vitro, human fibroblasts exposed to calpeptin, a pancalpain inhibitor, showed reduced collagen synthesis, impaired TGF beta-induced differentiation into alpha SMA-expressing myofibroblasts, and were less efficient in a collagen gel contraction assay. In conclusion, calpains are major players in granulation tissue formation. In view of their specific effects on fibroblasts a late inhibition of calpains should be considered for scar reduction

Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma

Mouse models of cancers are routinely used to study cancer biology. However, it remains unclear whether carcinogenesis in mice is driven by the same spectrum of genomic alterations found in humans. Here we conducted a comprehensive genomic analysis of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced skin cancer, the most commonly used skin cancer model, which appears as benign papillomas that progress into squamous cell carcinomas (SCCs). We also studied genetically induced SCCs that expressed G12D mutant Kras (Kras G12D) but were deficient for p53. Using whole-exome sequencing, we uncovered a characteristic mutational signature of DMBA-induced SCCs. We found that the vast majority of DMBA-induced SCCs presented recurrent mutations in Hras, Kras or Rras2 and mutations in several additional putative oncogenes and tumor-suppressor genes. Similar genes were recurrently mutated in mouse and human SCCs that were from different organs or had been exposed to different carcinogens. Invasive SCCs, but not papillomas, presented substantial chromosomal aberrations, especially in DMBA-induced and genetically induced Trp53-mutated SCCs. Metastasis occurred through sequential spreading, with relatively few additional genetic events. This study provides a framework for future functional cancer genomic studies in mice.status: publishe