In all mammals, foetal cells are transferred during pregnancy to the mothers. These foetal microchimeric cells (FMC) (a) persist in low amounts in maternal bone marrow for decades after delivery, (b) are well tolerated by the maternal immune system, (c) harbor progenitor cells and (d) are able to migrate to damaged maternal organs where these adopt the phenotype of the lesioned tissue. Our group has demonstrated the constant recruitment of foetal cells in maternal wounds were these cells differentiate mainly as endothelial cells. We later identified a specific subpopulation of FMC expressing CD34+CD11b+CD31+ that peaks early post maternal wounding. These cells over express CCR2 opening the possibility to selectively recruit such foetal cells. Therefore, injections of low, physiological doses of Ccl2 leads to the rescue of delayed cutaneous healing in females previously pregnant, but never in virgin mice (or those pregnant with a CCR2 KO fetuses). In the skin granulation tissue, FMC form foetal-derived vessels and promote maternal angiogenesis through various peptides, mainly CXCL1. This project aims to further characterize FMC ability to help maternal repair as well as to obtain proof of concept of Ccl2 to rescue maternal healing in the human species. We aim therefore to: 1) Perform an in-depth characterization of the potentialities of FMC in mice. We will use lineage tracing and clonal analysis in a Confetti mouse model in order to investigate the heterogeneity and stemness of FMC residing in mothers as well as those specifically recruited to skin wounds. We will also perform a transcriptional profiling of these cells at single-cell resolution to decipher their hierarchy and diversity. 2) Demonstrate the therapeutic potential of FMC in maternal tissue repair in vivo. We will test whether CCL2 is an efficient and safe therapy to recruit FMC in Sickle Cell Disease and diabetic mice models that present impaired wound healing. Both types of wounds are severe and incurable. In addition, we will test whether low doses of Ccl2 can be beneficial in extra-cutaneous maternal tissue repair models, such as the brain with brain excitoxic injections. 3) Characterize CCR2 levels in FMC in pregnant women or after delivery. We will assess the expression of CCR2 (receptor for Ccl2 on FMC) in cord blood from pregnant women presenting or not chronic wounds. To identify FMC in post-parous women, we will isolate cells harboring paternal unshared HLA antigens. Then, we will measure the level of CCR2 mRNA of FMC in post-parous women with or without chronic wounds either linked to sickle cell disease or to diabetes. In case, there is no over expression of CCR2 in FMC from wounded women, we will perform RNA sequencing analysis of these cell populations in order to identify other signaling pathways involved in the recruitment of FMC after maternal wounding. This project will help develop an original strategy of a “natural stem cell therapy” by mobilizing FMC to promote maternal tissue repair during pregnancy and after delivery. Upon success, our study will allow a rapid translation of this “natural stem cell therapy” to the bedside.