Fibrodysplasia ossificans progressiva (FOP), a congenital heterotopic ossification (HO) syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of skeletal muscles, tendons, ligaments, and joints. In this disease, HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1 knock-in allele recapitulate the phenotypic spectrum of FOP, including injury-responsive intramuscular HO and spontaneous articular, tendon, and ligament ossification. The cells that drive HO in these diverse tissues can be compartmentalized into two lineages: an Scx tendon-derived progenitor that mediates endochondral HO of ligaments and joints without exogenous injury, and a muscle-resident interstitial Mx1 population that mediates intramuscular, injury-dependent endochondral HO. Expression of Acvr1 in either lineage confers aberrant gain of BMP signaling and chondrogenic differentiation in response to activin A and gives rise to mutation-expressing hypertrophic chondrocytes in HO lesions. Compared to Acvr1, expression of the man-made, ligand-independent ACVR1 mutation accelerates and increases the penetrance of all observed phenotypes, but does not abrogate the need for antecedent injury in muscle HO, demonstrating the need for an injury factor in addition to enhanced BMP signaling. Both injury-dependent intramuscular and spontaneous ligament HO in Acvr1 knock-in mice were effectively controlled by the selective ACVR1 inhibitor LDN-212854. Thus, diverse phenotypes of HO found in FOP are rooted in cell-autonomous effects of dysregulated ACVR1 signaling in nonoverlapping tissue-resident progenitor pools that may be addressed by systemic therapy or by modulating injury-mediated factors involved in their local recruitment.
Background Despite the promise shown by stem cells for restoration of cardiac function following myocardial infarction (MI), the poor survival of transplanted cells has been a major issue. Hypoxia inducible factor-1 (HIF-1) is a transcription factor that mediates adaptive responses to ischemia. Here we hypothesize that co-delivery of cardiac progenitor cells (CPCs) with a nonviral minicircle plasmid carrying HIF-1 (MC-HIF1) into the ischemic myocardium can improve the survival of transplanted CPCs. Methods and Results Following MI, CPCs were co-delivered intramyocardially into adult NOD/SCID mice with either saline, MC-GFP, or MC-HIF1 versus MC-HIF1 alone (N=10/group). Bioluminescence imaging (BLI) demonstrated better survival when CPCs were co-delivered with MC-HIF1. Importantly, echocardiography showed mice injected with CPCs + MC-HIF1 had the highest ejection fraction 6 weeks post-MI (57.1±2.6%) followed by MC-HIF1 alone (48.5±2.6%), with no significant protection for CPCs + MC-GFP (44.8±3.3%) compared to saline control (38.7±3.2%, P<0.05). In vitro mechanistic studies confirmed that cardiac endothelial cells (ECs) produced exosomes which were actively internalized by recipient CPCs. Exosomes purified from ECs overexpressing HIF-1 had higher contents of miR-126 and miR-210. These microRNAs activated pro-survival kinases and induced a glycolytic switch in recipient CPCs, giving them increased tolerance when subjected to in vitro hypoxic stress. Inhibiting both of these miRs blocked the protective effects of the exosomes. Conclusions In summary, HIF-1 can be used to modulate the host microenvironment for improving survival of transplanted cells. The exosomal transfer of miRs from host cells to transplanted cells represents a unique mechanism that can be potentially targeted for improving survival of transplanted cells.
The exact nature of the immune response elicited by autologous induced pluripotent stem cell (iPSC) progeny is still not well understood. Here we show in murine models that autologous iPSC-derived endothelial cells (iECs) elicit an immune response that resembles the one against a comparable somatic cell, the aortic endothelial cell (AEC). These cells exhibit long-term survival in vivo and prompt a tolerogenic contexture of intra-graft characterized by elevated IL-10 expression. In contrast, undifferentiated iPSCs elicit a very different immune response with high lymphocytic infiltration and elevated IFN-γ, granzyme-B, and perforin intra-graft. Furthermore, the clonal structure of infiltrating T cells from iEC grafts is statistically indistinguishable from that of AECs, but is different from that of undifferentiated iPSC grafts. Taken together, our results indicate that the differentiation of iPSCs results in a loss of immunogenicity and leads to the induction of tolerance, despite expected antigen expression differences between iPSC-derived versus original somatic cells.
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