SOX17-mediated LPAR4 expression plays a pivotal role in cardiac development and regeneration after myocardial infarction
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Lysophosphatidic acid receptor 4 (LPAR4) exhibits transient expression at the cardiac progenitor stage during pluripotent stem cell (PSC)-derived cardiac differentiation. Using RNA sequencing, promoter analyses, and a loss-of-function study in human PSCs, we discovered that SRY-box transcription factor 17 (SOX17) is an essential upstream factor of LPAR4 during cardiac differentiation. We conducted mouse embryo analyses to further verify our human PSC in vitro findings and confirmed the transient and sequential expression of SOX17 and LPAR4 during in vivo cardiac development. In an adult bone marrow transplantation model using LPAR4 promoter-driven GFP cells, we observed two LPAR4+ cell types in the heart following myocardial infarction (MI). Cardiac differentiation potential was shown in heart-resident LPAR4+ cells, which are SOX17+, but not bone marrow-derived infiltrated LPAR4+ cells. Furthermore, we tested various strategies to enhance cardiac repair through the regulation of downstream signals of LPAR4. During the early stages following MI, the downstream inhibition of LPAR4 by a p38 mitogen-activated protein kinase (p38 MAPK) blocker improved cardiac function and reduced fibrotic scarring compared to that observed following LPAR4 stimulation. These findings improve our understanding of heart development and suggest novel therapeutic strategies that enhance repair and regeneration after injury by modulating LPAR4 signaling.
Abstract
Lysophosphatidic acid receptor 4 (LPAR4) exhibits transient expression at the cardiac progenitor stage during pluripotent stem cell (PSC)-derived cardiac differentiation. Using RNA sequencing, promoter analyses, and a loss-of-function study in human PSCs, we discovered that SRY-box transcription factor 17 (SOX17) is an essential upstream factor of LPAR4 during cardiac differentiation. We conducted mouse embryo analyses to further verify our human PSC in vitro findings and confirmed the transient and sequential expression of SOX17 and LPAR4 during in vivo cardiac development. In an adult bone marrow transplantation model using LPAR4 promoter-driven GFP cells, we observed two LPAR4+ cell types in the heart following myocardial infarction (MI). Cardiac differentiation potential was shown in heart-resident LPAR4+ cells, which are SOX17+, but not bone marrow-derived infiltrated LPAR4+ cells. Furthermore, we tested various strategies to enhance cardiac repair through the regulation of downstream signals of LPAR4. During the early stages following MI, the downstream inhibition of LPAR4 by a p38 mitogen-activated protein kinase (p38 MAPK) blocker improved cardiac function and reduced fibrotic scarring compared to that observed following LPAR4 stimulation. These findings improve our understanding of heart development and suggest novel therapeutic strategies that enhance repair and regeneration after injury by modulating LPAR4 signaling.
참고문헌 (27)
- Lee, C. S., "Identification of latrophilin-2 as a novel cell-surface marker for the cardiomyogenic lineage and its functional significance in heart development", Circulation, 139, pp.2910~2912 (2019)
- Vagnozzi, R. J., "An acute immune response underlies the benefit of cardiac stem cell therapy", Nature, 577, pp.405~409 (2020)
- Garbern, J. C., "Cardiac stem cell therapy and the promise of heart regeneration", Cell Stem Cell, 12, pp.689~698 (2013)
- Lee, J. W., "Lysophosphatidic acid receptor 4 is transiently expressed during cardiac differentiation and critical for repair of the damaged heart", Mol. Ther, 29, pp.1151~1163 (2021)
- Vizurraga, A., "Mechanisms of adhesion G protein-coupled receptor activation", J. Biol. Chem, 295, pp.14065~14083 (2020)
- Ito, C. Y., "Hematopoietic stem cell and progenitor defects in Sca-1", Ly-6A-null mice, 2003, pp.101, 517~523
- Morcos, M. N. F., "SCA-1 expression level identifies quiescent hematopoietic stem and progenitor cells", Stem Cell Rep, 8, pp.1472~1478 (2017)
- Cui, Y. Z., "Optimal protocol for total body irradiation for allogeneic bone marrow transplantation in mice", Bone Marrow Transplant, 30, pp.843~849 (2002)
- Duran-Struuck, R., "Principles of bone marrow transplantation(BMT) : providing optimal veterinary and husbandry care to irradiated mice in BMT studies", J. Am. Assoc. Lab. Anim. Sci, 48, pp.11~22 (2009)
- Pratumvinit, B., "Isolation, characterization, and transplantation of cardiac endothelial cells", Biomed. Res. Int, 2013, pp.359412~ (2013)
- Lacombe, F., "Flow cytometry CD45 gating for immunophenotyping of acute myeloid leukemia", Leukemia, 11, pp.1878~1886 (1997)
- Yao, Y., "SOX transcription factors in endothelial differentiation and endothelial-mesenchymal transitions", Front. Cardiovasc. Med, 6, pp.30~ (2019)
- Wang, P., "Targeting SOX17 in human embryonic stem cells creates unique strategies for isolating and analyzing developing endoderm", Cell Stem Cell, 8, pp.335~346 (2011)
- Silva, A. C., "Co-emergence of cardiac and gut tissues promotes cardiomyocyte maturation within human iPSC-derived organoids", Cell Stem Cell, 28, pp.2137~2152 (2021)
- Liu, Y., "Sox17 is essential for the specification of cardiac mesoderm in embryonic stem cells", Proc. Natl Acad. Sci. USA, 104, pp.3859~3864 (2007)
- Gessert, S., "The multiple phases and faces of Wnt signaling during cardiac differentiation and development", Circ. Res, 107, pp.186~199 (2010)
- Weil, B. R., "Selectins and immune cells in acute myocardial infarction and post-infarction ventricular remodeling : pathophysiology and novel treatments", Front. Immunol, 10, pp.300~ (2019)
- Kang, Y., "Administration of cardiac mesenchymal cells modulates innate immunity in the acute phase of myocardial infarction in mice", Sci. Rep, 10, pp.14754~ (2020)
- Igarashi, H., "The lysophosphatidic acid receptor LPA4 regulates hematopoiesis-supporting activity of bone marrow stromal cells", Sci. Rep, 5, pp.11410~ (2015)
- Anderson, D. J., "NKX2-5 regulates human cardiomyogenesis via a HEY2dependent transcriptional network", Nat. Commun, 9, pp.1373~ (2018)
- Lee, C. S., "Adhesion GPCR latrophilin-2 specifies cardiac lineage commitment through CDK5, Src, and P38MAPK", Stem Cell Rep, 16, pp.868~882 (2021)
- Chen, X., "MEF2 signaling and human diseases", Oncotarget, 8, pp.112152~112165 (2017)
- Arabacilar, P., "The case for inhibiting p38 mitogen-activated protein kinase in heart failure", Front. Pharmacol, 6, pp.102~ (2015)
- O’Donoghue, M. L., "Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction : a randomized clinical trial", JAMA, 315, pp.1591~1599 (2016)
- Strambu, I. R., "Phase II study of single", repeated doses of acumapimod (BCT197) to treat acute exacerbations of COPD, 2019, pp.16, 344~353
- Xing, L., "Clinical candidates of small molecule p38 MAPK inhibitors for inflammatory diseases", MAP Kinase, 4, pp.24~30 (2016)
- Molkentin, J. D., "Fibroblast-specific genetic manipulation of p38 mitogenactivated protein kinase in vivo reveals its central regulatory role in fibrosis", Circulation, 136, pp.549~561 (2017)