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

Effect of microchimerism and microbiota on cutaneous wound healing

La cicatrisation est un processus complexe, mettant en jeu plusieurs étapes qui sont l’inflammation, la prolifération et le remodelage, le but étant de restaurer la fonction barrière de la peau. Des cellules fœtales passent lors de la gestation dans la circulation maternelle et nichent au sein de la moelle osseuse. Ces dernières peuvent être attirées au niveau de la plaie et participer à l’étape d’angiogenèse. C’est une population hétérogène composée de cellules différenciées et de progéniteurs. La sous-population CD11b+ CD34+ CD31+ est recrutée de manière précoce par la voie de signalisation CCL2/CCR2 et présente un pouvoir de différenciation ainsi qu’un phénotype sécrétoire bien plus important que son homologue adulte. Elle se différencie en cellules endothéliales et en péricytes afin de participer directement à la vasculogenèse maternelle ou alors de sécréter certains facteurs pro-angiogeniques tel que CXCL1. Dans un modèle de cicatrisation altérée en condition post-partum, les cellules fœtales suite à l’administration de CCL2, sont recrutées sur le site lésionnel et permettent l’amélioration de la cicatrisation. Par la suite, nous avons mis en évidence le rôle du microbiote de la peau sur la réparation cutanée. La colonisation de la lésion par des bactéries commensales de la peau telle que Pasteurella spp permet une meilleure réponse immunitaire ainsi qu’une augmentation de l’angiogenèse aboutissant à une accélération de la cinétique de cicatrisation en comparaison à un environnement dénué de tout agent pathogène. Le produit de lyse bactérienne permet de mimer l’infection et de restaurer en partie la cascade de signalisation aboutissant à la fermeture de la plaie.Wound healing is a complex process, involving many stages, which are inflammation, proliferation and remodelling, to repair the barrier function of the skin. Fetal cells pass into maternal circulation and nest in the bone marrow. These cells are triggered to injured tissue and participate to angiogenesis. It is a heterogeneous population, composed of differentiated cells and progenitors. The subpopulation CD11b+ CD34+ CD31+ is early recruited through the signalling pathway CCL2/CCR2, have greater differentiating potential and a better secreting phenotype than its adult counterpart. Fetal cells can differentiate into endothelial cells and pericytes to directly participate to maternal neovascularization or secrete pro-angiogenic factors like CXCL1. In a delay wound healing model in postpartum condition, fetal cells after CCL2 administration are recruited into the wound tissue and improved wound healing process. After that, we evaluated the role of the skin microbiota, which can modulate skin wound healing. The injured skin colonization by commensal bacteria like Pasteurella spp leads to and improvement of inflammation, angiogenesis and an increased of the kinetic of the wound healing compare to a environment without any pathogen specific. Lysate product from bacteria can mimic the infection and partially restores the signalling pathway leading to wound closure

Clinical Value and Molecular Function of Circulating MicroRNAs in Endometrial Cancer Regulation: A Systematic Review

This systematic review of literature highlights the different microRNAs circulating in the serum or plasma of endometrial cancer patients and their association with clinical and prognostic characteristics in endometrial cancer. This study also investigates the molecular functions of these circulating microRNAs. According to this systematic review, a total of 33 individual circulating miRs (-9, -15b, -20b-5p, -21, -27a, -29b, -30a-5p, -92a, -99a, -100, -135b, -141, -142-3p, -143-3p, -146a-5p, -150-5p, -151a-5p, -186, -195-5p, -199b, -200a, -203, -204, -205, -222, -223, -301b, -423-3p, -449, -484, -887-5p, -1228, and -1290) and 6 different panels of miRs (“miR-222/miR-223/miR-186/miR-204”, “miR-142-3p/miR-146a-5p/miR-151a-5p”, “miR-143-3p/miR-195-5p/miR-20b-5p/miR-204-5p/miR-423-3p/miR-484”, “mir-9/miR-1229”, “miR-9/miR-92a”, and “miR-99a/miR-199b”) had a significant expression variation in EC patients compared to healthy patients. Also, seven individual circulating miRs (-9, -21, -27a, -29b, -99a, -142-3p, and -449a) had a significant expression variation according to EC prognostic factors such as the histological type and grade, tumor size, FIGO stage, lymph node involvement, and survival rates. One panel of circulating miRs (“-200b/-200c/-203/-449a”) had a significant expression variation according to EC myometrial invasion. Further studies are needed to better understand their function and circulation

Clinical Value and Molecular Function of Circulating MicroRNAs in Endometrial Cancer Regulation: A Systematic Review

This systematic review of literature highlights the different microRNAs circulating in the serum or plasma of endometrial cancer patients and their association with clinical and prognostic characteristics in endometrial cancer. This study also investigates the molecular functions of these circulating microRNAs. According to this systematic review, a total of 33 individual circulating miRs (-9, -15b, -20b-5p, -21, -27a, -29b, -30a-5p, -92a, -99a, -100, -135b, -141, -142-3p, -143-3p, -146a-5p, -150-5p, -151a-5p, -186, -195-5p, -199b, -200a, -203, -204, -205, -222, -223, -301b, -423-3p, -449, -484, -887-5p, -1228, and -1290) and 6 different panels of miRs (“miR-222/miR-223/miR-186/miR-204”, “miR-142-3p/miR-146a-5p/miR-151a-5p”, “miR-143-3p/miR-195-5p/miR-20b-5p/miR-204-5p/miR-423-3p/miR-484”, “mir-9/miR-1229”, “miR-9/miR-92a”, and “miR-99a/miR-199b”) had a significant expression variation in EC patients compared to healthy patients. Also, seven individual circulating miRs (-9, -21, -27a, -29b, -99a, -142-3p, and -449a) had a significant expression variation according to EC prognostic factors such as the histological type and grade, tumor size, FIGO stage, lymph node involvement, and survival rates. One panel of circulating miRs (“-200b/-200c/-203/-449a”) had a significant expression variation according to EC myometrial invasion. Further studies are needed to better understand their function and circulation.</jats:p

Ccl2/Ccr2 signalling recruits a distinct fetal microchimeric population that rescues delayed maternal wound healing

International audienceFoetal microchimeric cells (FMCs) traffic into maternal circulation during pregnancy and persist for decades after delivery. Upon maternal injury, FMCs migrate to affected sites where they participate in tissue healing. However, the specific signals regulating the trafficking of FMCs to injury sites had to be identified. Here we report that, in mice, a subset of FMCs implicated in tissue repair displays CD11b+ CD34+ CD31+ phenotype and highly express C-C chemokine receptor 2 (Ccr2). The Ccr2 ligand chemokine ligand 2 (Ccl2) enhances the recruitment of FMCs to maternal wounds where these cells transdifferentiate into endothelial cells and stimulate angiogenesis through Cxcl1 secretion. Ccl2 administration improves delayed maternal wound healing in pregnant and postpartum mice but never in virgin ones. This role of Ccl2/Ccr2 signalling opens new strategies for tissue repair through natural stem cell therapy, a concept that can be later applied to other types of maternal diseases

Characterization of a Cutibacterium acnes Camp Factor 1-Related Peptide as a New TLR-2 Modulator in In Vitro and Ex Vivo Models of Inflammation

Cutibacterium acnes (C. acnes) has been implicated in inflammatory acne where highly mutated Christie–Atkins–Munch–Petersen factor (CAMP)1 displays strong toll like receptor (TLR)-2 binding activity. Using specific antibodies, we showed that CAMP1 production was independent of C. acnes phylotype and involved in the induction of inflammation. We confirmed that TLR-2 bound both mutated and non-mutated recombinant CAMP1, and peptide array analysis showed that seven peptides (A14, A15, B1, B2, B3, C1 and C3) were involved in TLR-2 binding, located on the same side of the three-dimensional structure of CAMP1. Both mutated and non-mutated recombinant CAMP1 proteins induced the production of C-X-C motif chemokine ligand interleukin (CXCL)8/(IL)-8 in vitro in keratinocytes and that of granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, IL-1β and IL-10 in ex vivo human skin explants. Only A14, B1 and B2 inhibited the production of CXCL8/IL-8 by keratinocytes and that of (GM-CSF), TNF-α, IL-1β and IL-10 in human skin explants stimulated with rCAMP1 and C. acnes. Following pretreatment with B2, RNA sequencing on skin explants identified the 10 genes displaying the strongest differential expression as IL6, TNF, CXCL1, CXCL2, CXCL3, CXCL8, IL-1β, chemokine ligand (CCL)2, CCL4 and colony stimulating factor (CSF)2. We, thus, identified a new CAMP1-derived peptide as a TLR-2 modulator likely to be a good candidate for clinical evaluation.</jats:p

Characterization of a Cutibacterium Acnes Camp Factor 1-Related Peptide as a New TLR-2 Modulator in In Vitro and Ex Vivo Models of Inflammation

Cutibacterium acnes (C. acnes) has been implicated in inflammatory acne where highly mutated Christie\textendash Atkins\textendash Munch\textendash Petersen factor (CAMP)1 displays strong toll like receptor (TLR)-2 binding activity. Using specific antibodies, we showed that CAMP1 production was independent of C. acnes phylotype and involved in the induction of inflammation. We confirmed that TLR-2 bound both mutated and non-mutated recombinant CAMP1, and peptide array analysis showed that seven peptides (A14, A15, B1, B2, B3, C1 and C3) were involved in TLR-2 binding, located on the same side of the three-dimensional structure of CAMP1. Both mutated and non-mutated recombinant CAMP1 proteins induced the production of C-X-C motif chemokine ligand interleukin (CXCL)8/(IL)-8 in vitro in keratinocytes and that of granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, IL-1β and IL-10 in ex vivo human skin explants. Only A14, B1 and B2 inhibited the production of CXCL8/IL-8 by keratinocytes and that of (GM-CSF), TNF-α, IL-1β and IL-10 in human skin explants stimulated with rCAMP1 and C. acnes. Following pretreatment with B2, RNA sequencing on skin explants identified the 10 genes displaying the strongest differential expression as IL6, TNF, CXCL1, CXCL2, CXCL3, CXCL8, IL-1β, chemokine ligand (CCL)2, CCL4 and colony stimulating factor (CSF)2. We, thus, identified a new CAMP1-derived peptide as a TLR-2 modulator likely to be a good candidate for clinical evaluation

MicroRNA as Epigenetic Modifiers in Endometrial Cancer: A Systematic Review

International audienceThe objective of this systematic review is to summarize our current knowledge on the influence of miRNAs in the epigenetic deregulation of tumor-related genes in endometrial cancer (EC). We conducted a literature search on the role of miRNAs in the epigenetic regulation of EC applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following terms were used: microRNA, miRNA, miR, endometrial cancer, endometrium, epigenetic, epimutation, hypermethylation, lynch, deacetylase, DICER, novel biomarker, histone, chromatin. The miRNAs were classified and are presented according to their function (tumor suppressor or onco-miRNA), their targets (when known), their expression levels in EC tissue vs the normal surrounding tissue, and the degree of DNA methylation in miRNA loci and CpG sites. Data were collected from 201 articles, including 190 original articles, published between November 1, 2008 and September 30, 2020 identifying 313 different miRNAs implicated in epigenetic regulation of EC. Overall, we identified a total of 148 miRNAs with decreased expression in EC, 140 miRNAs with increased expression in EC, and 22 miRNAs with discordant expression levels. The literature implicated different epigenetic phenomena including altered miRNA expression levels (miR-182, -230), changes in the methylation of miRNA loci (miR-34b, -129-2, -130a/b, -152, -200b, -625) and increased/decreased methylation of target genes (miR-30d,-191). This work provides an overview of all miRNAs reported to be involved in epigenetic regulation in EC including DNA methylation and RNA-associated silencing. These findings may contribute to novel strategies in diagnosis, risk assessment, and treatments aimed at miRNAs, their target genes or DNA methylation. View Full-Tex