Placental immune responses are highly regulated to strike a balance between protection and tolerance. For relatively mild infections, protection encompasses both the mother and fetus; however, during worsening conditions, protection becomes exclusively reserved for the mother. Previously, we and others have shown that the host factor perforin-2 plays a central role in protecting mice and cells against infection. In this study, we analyzed perforin-2 activity in the mouse placenta to determine whether perforin-2 plays a similarly protective role. We show that perforin-2 is critical for inhibiting Listeria monocytogenes colonization of the placenta and fetus and that this protection is due to both maternal and fetal-encoded perforin-2. Perforin-2 mRNA is readily detectable in individual immune cells of the decidua, and these levels are further enhanced specifically in decidual macrophages during high-dose infections that result in fetal expulsion. Unexpectedly, inductive perforin-2 expression in decidual macrophages did not occur during milder infections in which fetal viability remained intact. This pattern of expression significantly differed from that observed in splenic macrophages in which inductive perforin-2 expression was observed in both high and mild infection conditions. In the placenta, inductive perforin-2 expression in decidual macrophages was coincident with their polarization from a CD206 + MHC class II lo to CD206 2 MHC class II hi phenotype that normally occurs in the placenta during high-burden infections. Our results suggest that perforin-2 is part of a host response that is protective either for both the mother and fetus in milder infections or exclusively for the mother during high-dose infections.
We propose that GDNF, a glial cell line‐derived neurotrophic factor, can promote hair follicle neogenesis and skin regeneration after wounding by directing the fate of dermal fibroblasts. Our hypothesis is largely based on detailed GDNF and receptor analysis during skin regenerative stages, as well as the induction of GDNF receptors after wounding between the pro‐regenerative spiny mouse (genus Acomys) and its less‐regenerative descendant, the house mouse (Mus musculus). To characterize the GDNF‐target cells, we will conduct a series of lineage‐tracing experiments in conjunction with single‐cell RNA and assay for transposase‐accessible chromatin sequencing experiments. The heterogenetic dynamics of skin regeneration have yet to be fully defined, and this research will help to advance the fields of regenerative medicine and biology. Finally, we believe that stimulating the GDNF signalling pathway in fibroblasts from less‐regenerative animals, such as humans, will promote skin regeneration, morphogenesis and scarless wound healing.
Osteosarcomas are immune-resistant and metastatic in part due to an increase in nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT) induction. In this study, we examined the impact of vitamin D3 and its receptor (VDR) on the NMD-ROS-EMT signaling axis in osteosarcoma cells and spheroids, as well as wound-induced cell migration and osteosarcoma metastasis in vivo models. Activated VDR signaling enriched the EMT pathway in gene set enrichment analysis, whereas the active vitamin D3 metabolite, 1,25(OH)2D, inhibited EMT in osteosarcoma subtypes. Because EMT processes in cancer and tissue wounds are similar, experimentally induced EMT of mouse hair follicle stem cells revealed that Vdr signaling restricts cell migration during cutaneous wound healing. In osteosarcoma cells, ligand bound VDR inhibited EMT by interacting directly with and downregulating the EMT inducer SNAI2. Differential epigenetic regulation of SNAI2 and VDR distinguished highly metastatic from low metastatic osteosarcoma subtypes and responsiveness to 1,25(OH)2D. Furthermore, epigenome-wide motif and putative target gene analysis revealed the integration of the VDR with the NMD tumor immunogenic pathway. In an autoregulatory manner, 1,25(OH)2D inhibited NMD machinery genes, while simultaneously inducing the overexpression of known NMD target genes involved in tumor immune recognition and cell-to-cell adhesion. Dicer substrate siRNA knockdown of SNAI2 revealed superoxide dismutase 2 (SOD2)-mediated antioxidative responses and 1,25(OH)2D sensitization, which involves the non-canonical SOD2 nuclear-to-mitochondrial translocalization and inhibition of ROS. Calcipotriol, a clinically relevant non-calcemic vitamin D3 derivative, inhibited osteosarcoma metastasis in a mouse xenograft model. Our research reveals novel vitamin D3 and calcipotriol osteosarcoma-inhibiting processes.
Osteosarcomas are immune-resistant and metastatic as a result of elevated nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT). Although vitamin D has anti-cancer effects, its effectiveness and mechanism of action against osteosarcomas are poorly understood. In this study, we assessed the impact of vitamin D and its receptor (VDR) on NMD-ROS-EMT signaling in in vitro and in vivo osteosarcoma animal models. Initiation of VDR signaling facilitated the enrichment of EMT pathway genes, after which 1,25(OH)2D, the active vitamin D derivative, inhibited the EMT pathway in osteosarcoma subtypes. The ligand-bound VDR directly downregulated the EMT inducer SNAI2, differentiating highly metastatic from low metastatic subtypes and 1,25(OH)2D sensitivity. Moreover, epigenome-wide motif and putative target gene analysis revealed the VDR’s integration with NMD tumorigenic and immunogenic pathways. In an autoregulatory manner, 1,25(OH)2D inhibited NMD machinery genes and upregulated NMD target genes implicated in anti-oncogenic activity, immunorecognition, and cell-to-cell adhesion. Dicer substrate siRNA knockdown of SNAI2 revealed superoxide dismutase 2 (SOD2)-mediated antioxidative responses and 1,25(OH)2D sensitization via non-canonical SOD2 nuclear-to-mitochondrial translocalization leading to overall ROS suppression. In a mouse xenograft metastasis model, the therapeutically relevant vitamin D derivative calcipotriol inhibited osteosarcoma metastasis and tumor growth shown for the first time. Our results uncover novel osteosarcoma-inhibiting mechanisms for vitamin D and calcipotriol that may be translated to human patients.
21Placental immune responses are highly regulated to strike a balance between protection and 22 tolerance. For relatively mild infections, protection encompasses both the mother and fetus; 23 however, during worsening conditions, protection becomes exclusively reserved for the mother. 24Previously, we and others have shown that the host factor Perforin-2 plays a central role in 25 protecting mice and cells against infection. Here, we analyzed Perforin-2 activity in the mouse 26 placenta to determine whether Perforin-2 plays a similarly protective role. We show that Perforin-27 2 is critical for inhibiting Listeria monocytogenes colonization of the placenta and fetus and that 28 this protection is due to both maternal and fetal-encoded Perforin-2. Perforin-2 mRNA is readily 29 detectable in individual immune cells of the decidua and these levels are further enhanced 30 specifically in decidual macrophages during high-dose infections that result in fetal expulsion. 31Unexpectedly, inductive Perforin-2 expression in decidual macrophages did not occur during 32 milder infections in which fetal viability remained intact. This pattern of expression significantly 33 differed from that observed in splenic macrophages in which inductive Perforin-2 expression was 34 observed in both high and mild infection conditions. In the placenta, inductive Perforin-2 35 expression in decidual macrophages was co-incident with their polarization from a M2 to M1 36 phenotype that normally occurs in the placenta during high-burden infections. Our results suggest 37 that Perforin-2 is part of a host response that is protective either for both the mother and fetus in 38 milder infections or exclusively for the mother during high-dose infections.
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