Niranjana Natarajan1, Yamen Abbas1, Donald M Bryant1,2,3, Juan Manuel Gonzalez-Rosa4, Michka Sharpe4, Aysu Uygur1, Lucas H Cocco-Delgado1, Nhi Ngoc Ho1, Norma P Gerard5,6,7, Craig J Gerard5,6,7, Calum A MacRae8, Caroline E Burns4, C Geoffrey Burns4, Jessica L Whited1,2,3, Richard T Lee9,8. 1. Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (N.N., Y.A., D.M.B., A.U., L.H.C.-D., N.N.H., J.L.W., R.T.L.). 2. Department of Orthopedic Surgery, Brigham & Women's Hospital, Cambridge, MA (D.M.B., J.L.W.). 3. Allen Discovery Center, Tufts University, Medford, MA (D.M.B., J.L.W.). 4. Harvard Medical School and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA (J.M.G.-R., M.S., C.E.B., C.G.B.). 5. Division of Respiratory Diseases, Boston Children's Hospital, MA (C.J.G., N.P.G.). 6. Department of Medicine, Harvard Medical School, Boston, MA (C.J.G., N.P.G.). 7. Beth Israel Deaconess Medical Center, Boston, MA (C.J.G., N.P.G.). 8. Department of Medicine, Cardiovascular Division, Brigham & Women's Hospital and Harvard Medical School, Boston, MA (C.A.M., R.T.L.). 9. Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (N.N., Y.A., D.M.B., A.U., L.H.C.-D., N.N.H., J.L.W., R.T.L.) Richard_Lee@harvard.edu.
Abstract
BACKGROUND: Defining conserved molecular pathways in animal models of successful cardiac regeneration could yield insight into why adult mammals have inadequate cardiac regeneration after injury. Insight into the transcriptomic landscape of early cardiac regeneration from model organisms will shed light on evolutionarily conserved pathways in successful cardiac regeneration. METHODS: Here we describe a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration: axolotl, neonatal mice, and zebrafish. Apical resection to remove ≈10% to 20% of ventricular mass was carried out in these model organisms. RNA-sequencing analysis was performed on the hearts harvested at 3 time points: 12, 24, and 48 hours after resection. Sham surgery was used as internal control. RESULTS: Genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors (activated by complement components, part of the innate immune system) were found to be highly upregulated in all 3 species. This approach revealed induction of gene expression for complement 5a receptor 1 in the regenerating hearts of zebrafish, axolotls, and mice. Inhibition of complement 5a receptor 1 significantly attenuated the cardiomyocyte proliferative response to heart injury in all 3 species. Furthermore, after left ventricular apical resection, the cardiomyocyte proliferative response was diminished in mice with genetic deletion of complement 5a receptor 1. CONCLUSIONS: These data reveal that activation of complement 5a receptor 1 mediates an evolutionarily conserved response that promotes cardiomyocyte proliferation after cardiac injury and identify complement pathway activation as a common pathway of successful heart regeneration.
BACKGROUND: Defining conserved molecular pathways in animal models of successful cardiac regeneration could yield insight into why adult mammals have inadequate cardiac regeneration after injury. Insight into the transcriptomic landscape of early cardiac regeneration from model organisms will shed light on evolutionarily conserved pathways in successful cardiac regeneration. METHODS: Here we describe a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration: axolotl, neonatal mice, and zebrafish. Apical resection to remove ≈10% to 20% of ventricular mass was carried out in these model organisms. RNA-sequencing analysis was performed on the hearts harvested at 3 time points: 12, 24, and 48 hours after resection. Sham surgery was used as internal control. RESULTS: Genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors (activated by complement components, part of the innate immune system) were found to be highly upregulated in all 3 species. This approach revealed induction of gene expression for complement 5a receptor 1 in the regenerating hearts of zebrafish, axolotls, and mice. Inhibition of complement 5a receptor 1 significantly attenuated the cardiomyocyte proliferative response to heart injury in all 3 species. Furthermore, after left ventricular apical resection, the cardiomyocyte proliferative response was diminished in mice with genetic deletion of complement 5a receptor 1. CONCLUSIONS: These data reveal that activation of complement 5a receptor 1 mediates an evolutionarily conserved response that promotes cardiomyocyte proliferation after cardiac injury and identify complement pathway activation as a common pathway of successful heart regeneration.
Authors: Arin B Aurora; Enzo R Porrello; Wei Tan; Ahmed I Mahmoud; Joseph A Hill; Rhonda Bassel-Duby; Hesham A Sadek; Eric N Olson Journal: J Clin Invest Date: 2014-02-24 Impact factor: 14.808
Authors: Donald M Bryant; Kimberly Johnson; Tia DiTommaso; Timothy Tickle; Matthew Brian Couger; Duygu Payzin-Dogru; Tae J Lee; Nicholas D Leigh; Tzu-Hsing Kuo; Francis G Davis; Joel Bateman; Sevara Bryant; Anna R Guzikowski; Stephanie L Tsai; Steven Coyne; William W Ye; Robert M Freeman; Leonid Peshkin; Clifford J Tabin; Aviv Regev; Brian J Haas; Jessica L Whited Journal: Cell Rep Date: 2017-01-17 Impact factor: 9.423
Authors: Andreas D Niederbichler; Laszlo M Hoesel; Margaret V Westfall; Hongwei Gao; Kyros R Ipaktchi; Lei Sun; Firas S Zetoune; Grace L Su; Saman Arbabi; J Vidya Sarma; Stewart C Wang; Mark R Hemmila; Peter A Ward Journal: J Exp Med Date: 2005-12-27 Impact factor: 14.307
Authors: Raz Ben-Yair; Vincent L Butty; Michele Busby; Yutong Qiu; Stuart S Levine; Alon Goren; Laurie A Boyer; C Geoffrey Burns; Caroline E Burns Journal: Development Date: 2019-10-09 Impact factor: 6.868
Authors: Lilian Grigorian Shamagian; Rosalinda Madonna; Doris Taylor; Andreu M Climent; Felipe Prosper; Luis Bras-Rosario; Antoni Bayes-Genis; Péter Ferdinandy; Francisco Fernández-Avilés; Juan Carlos Izpisua Belmonte; Valentin Fuster; Roberto Bolli Journal: Circ Res Date: 2019-03-15 Impact factor: 17.367
Authors: Nataliya Timoshevskaya; S Randal Voss; Caitlin N Labianca; Cassity R High; Jeramiah J Smith Journal: Dev Dyn Date: 2020-10-14 Impact factor: 3.780