Skip to main content

Advertisement

SpringerLink
Log in

Thrombospondin 1 and Reelin act through Vldlr to regulate cardiac growth and repair

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Adult mammalian cardiomyocytes have minimal cell cycle capacity, which leads to poor regeneration after cardiac injury such as myocardial infarction. Many positive regulators of cardiomyocyte cell cycle and cardioprotective signals have been identified, but extracellular signals that suppress cardiomyocyte proliferation are poorly understood. We profiled receptors enriched in postnatal cardiomyocytes, and found that very-low-density-lipoprotein receptor (Vldlr) inhibits neonatal cardiomyocyte cell cycle. Paradoxically, Reelin, the well-known Vldlr ligand, expressed in cardiac Schwann cells and lymphatic endothelial cells, promotes neonatal cardiomyocyte proliferation. Thrombospondin1 (TSP-1), another ligand of Vldlr highly expressed in adult heart, was then found to inhibit cardiomyocyte proliferation through Vldlr, and may contribute to Vldlr’s overall repression on proliferation. Mechanistically, Rac1 and subsequent Yap phosphorylation and nucleus translocation mediate the regulation of the cardiomyocyte cell cycle by TSP-1/Reelin-Vldlr signaling. Importantly, Reln mutant neonatal mice displayed impaired cardiomyocyte proliferation and cardiac regeneration after apical resection, while cardiac-specific Thbs1 deletion and cardiomyocyte-specific Vldlr deletion promote cardiomyocyte proliferation and are cardioprotective after myocardial infarction. Our results identified a novel role of Vldlr in consolidating extracellular signals to regulate cardiomyocyte cell cycle activity and survival, and the overall suppressive TSP-1-Vldlr signal may contribute to the poor cardiac repair capacity of adult mammals.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data availability

Source data are provided with this paper. RNA-Seq data including all raw sequence files and processed files have been deposited in the Gene Expression Omnibus under the accession number GSE176009. RNA-seq data from published papers used in this study is GSE155658. sc-RNA-seq data from published papers used in this study include: GSE122706, E-MTAB-6173, E-MTAB-8077. Any additional data supporting this study will be made available by the corresponding author upon reasonable request.

References

  1. Agah R, Frenkel PA, French BA, Michael LH, Overbeek PA, Schneider MD (1997) Gene recombination in postmitotic cells. targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo. J Clin Invest 100:169–179. https://doi.org/10.1172/JCI119509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Aharonov A, Shakked A, Umansky KB, Savidor A, Genzelinakh A, Kain D, Lendengolts D, Revach OY, Morikawa Y, Dong J, Levin Y, Geiger B, Martin JF, Tzahor E (2020) ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration. Nat Cell Biol 22:1346–1356. https://doi.org/10.1038/s41556-020-00588-4

    Article  CAS  PubMed  Google Scholar 

  3. Ali H, Braga L, Giacca M (2020) Cardiac regeneration and remodelling of the cardiomyocyte cytoarchitecture. FEBS J 287:417–438. https://doi.org/10.1111/febs.15146

    Article  CAS  PubMed  Google Scholar 

  4. Atanasova VS, Russell RJ, Webster TG, Cao Q, Agarwal P, Lim YZ, Krishnan S, Fuentes I, Guttmann-Gruber C, McGrath JA, Salas-Alanis JC, Fertala A, South AP (2019) Thrombospondin-1 Is a major activator of tgf-beta signaling in recessive dystrophic epidermolysis bullosa fibroblasts. J Invest Dermatol 139(1497–1505):e1495. https://doi.org/10.1016/j.jid.2019.01.011

    Article  CAS  Google Scholar 

  5. Bassat E, Mutlak YE, Genzelinakh A, Shadrin IY, Baruch Umansky K, Yifa O, Kain D, Rajchman D, Leach J, Riabov Bassat D, Udi Y, Sarig R, Sagi I, Martin JF, Bursac N, Cohen S, Tzahor E (2017) The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 547:179–184. https://doi.org/10.1038/nature22978

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J (2009) Evidence for cardiomyocyte renewal in humans. Science 324:98–102. https://doi.org/10.1126/science.1164680

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Biro M, Munoz MA, Weninger W (2014) Targeting Rho-GTPases in immune cell migration and inflammation. Br J Pharmacol 171:5491–5506. https://doi.org/10.1111/bph.12658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Blake SM, Strasser V, Andrade N, Duit S, Hofbauer R, Schneider WJ, Nimpf J (2008) Thrombospondin-1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration. EMBO J 27:3069–3080. https://doi.org/10.1038/emboj.2008.223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bosch C, Muhaisen A, Pujadas L, Soriano E, Martinez A (2016) Reelin exerts structural, biochemical and transcriptional regulation over presynaptic and postsynaptic elements in the adult hippocampus. Front Cell Neurosci 10:138. https://doi.org/10.3389/fncel.2016.00138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bosco EE, Mulloy JC, Zheng Y (2009) Rac1 GTPase: a “Rac” of all trades. Cell Mol Life Sci 66:370–374. https://doi.org/10.1007/s00018-008-8552-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cardoso AC, Lam NT, Savla JJ, Nakada Y, Pereira AHM, Elnwasany A, Menendez-Montes I, Ensley EL, Petric UB, Sharma G, Sherry AD, Malloy CR, Khemtong C, Kinter MT, Tan WLW, Anene-Nzelu CG, Foo RS, Nguyen NUN, Li S, Ahmed MS, Elhelaly WM, Abdisalaam S, Asaithamby A, Xing C, Kanchwala M, Vale G, Eckert KM, Mitsche MA, McDonald JG, Hill JA, Huang L, Shaul PW, Szweda LI, Sadek HA (2020) Mitochondrial substrate utilization regulates cardiomyocyte cell cycle progression. Nat Metab 2:167–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Carpenter AE, Jones TR, Lamprecht MR, Clarke C, Kang IH, Friman O, Guertin DA, Chang JH, Lindquist RA, Moffat J, Golland P, Sabatini DM (2006) Cell profiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol 7:R100. https://doi.org/10.1186/gb-2006-7-10-r100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Caviness VS Jr, So DK, Sidman RL (1972) The hybrid reeler mouse. J Hered 63:241–246. https://doi.org/10.1093/oxfordjournals.jhered.a108286

    Article  PubMed  Google Scholar 

  14. Cocito C, Merighi A, Giacobini M, Lossi L (2016) Alterations of cell proliferation and apoptosis in the hypoplastic reeler cerebellum. Front Cell Neurosci 10:141. https://doi.org/10.3389/fncel.2016.00141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, Inui M, Montagner M, Parenti AR, Poletti A, Daidone MG, Dupont S, Basso G, Bicciato S, Piccolo S (2011) The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147:759–772. https://doi.org/10.1016/j.cell.2011.09.048

    Article  CAS  PubMed  Google Scholar 

  16. D’Uva G, Aharonov A, Lauriola M, Kain D, Yahalom-Ronen Y, Carvalho S, Weisinger K, Bassat E, Rajchman D, Yifa O, Lysenko M, Konfino T, Hegesh J, Brenner O, Neeman M, Yarden Y, Leor J, Sarig R, Harvey RP, Tzahor E (2015) ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat Cell Biol 17:627–638. https://doi.org/10.1038/ncb3149

    Article  CAS  PubMed  Google Scholar 

  17. Dharmawardhane S, Hernandez E, Vlaar C (2013) Development of EHop-016: a small molecule inhibitor of Rac. Enzymes 33:117–146. https://doi.org/10.1016/B978-0-12-416749-0.00006-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Diez-Cunado M, Wei K, Bushway PJ, Maurya MR, Perera R, Subramaniam S, Ruiz-Lozano P, Mercola M (2018) miRNAs that Induce human cardiomyocyte proliferation converge on the hippo pathway. Cell Rep 23:2168–2174. https://doi.org/10.1016/j.celrep.2018.04.049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dlugosz P, Nimpf J (2018) The reelin receptors apolipoprotein E receptor 2 (ApoER2) and VLDL receptor. Int J Mol Sci. https://doi.org/10.3390/ijms19103090

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S (2011) Role of YAP/TAZ in mechanotransduction. Nature 474:179–183. https://doi.org/10.1038/nature10137

    Article  CAS  PubMed  Google Scholar 

  21. Fan F, He Z, Kong LL, Chen Q, Yuan Q, Zhang S, Ye J, Liu H, Sun X, Geng J, Yuan L, Hong L, Xiao C, Zhang W, Sun X, Li Y, Wang P, Huang L, Wu X, Ji Z, Wu Q, Xia NS, Gray NS, Chen L, Yun CH, Deng X, Zhou D (2016) Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci Transl Med 8:352ra108. https://doi.org/10.1126/scitranslmed.aaf2304

    Article  CAS  PubMed  Google Scholar 

  22. Frykman PK, Brown MS, Yamamoto T, Goldstein JL, Herz J (1995) Normal plasma lipoproteins and fertility in gene-targeted mice homozygous for a disruption in the gene encoding very low density lipoprotein receptor. Proc Natl Acad Sci U S A 92:8453–8457. https://doi.org/10.1073/pnas.92.18.8453

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gan P, Patterson M, Sucov HM (2020) Cardiomyocyte polyploidy and implications for heart regeneration. Annu Rev Physiol 82:45–61. https://doi.org/10.1146/annurev-physiol-021119-034618

    Article  CAS  PubMed  Google Scholar 

  24. Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279:509–514. https://doi.org/10.1126/science.279.5350.509

    Article  ADS  CAS  PubMed  Google Scholar 

  25. Hesse M, Doengi M, Becker A, Kimura K, Voeltz N, Stein V, Fleischmann BK (2018) Midbody positioning and distance between daughter nuclei enable unequivocal identification of cardiomyocyte cell division in mice. Circ Res 123:1039–1052. https://doi.org/10.1161/CIRCRESAHA.118.312792

    Article  CAS  PubMed  Google Scholar 

  26. Hill MC, Kadow ZA, Long H, Morikawa Y, Martin TJ, Birks EJ, Campbell KS, Nerbonne J, Lavine K, Wadhwa L, Wang J, Turaga D, Adachi I, Martin JF (2022) Integrated multi-omic characterization of congenital heart disease. Nature 608:181–191. https://doi.org/10.1038/s41586-022-04989-3

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hirose K, Payumo AY, Cutie S, Hoang A, Zhang H, Guyot R, Lunn D, Bigley RB, Yu H, Wang J, Smith M, Gillett E, Muroy SE, Schmid T, Wilson E, Field KA, Reeder DM, Maden M, Yartsev MM, Wolfgang MJ, Grutzner F, Scanlan TS, Szweda LI, Buffenstein R, Hu G, Flamant F, Olgin JE, Huang GN (2019) Evidence for hormonal control of heart regenerative capacity during endothermy acquisition. Science 364:184–188. https://doi.org/10.1126/science.aar2038

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hu W, Jiang A, Liang J, Meng H, Chang B, Gao H, Qiao X (2008) Expression of VLDLR in the retina and evolution of subretinal neovascularization in the knockout mouse model’s retinal angiomatous proliferation. Invest Ophthalmol Vis Sci 49:407–415. https://doi.org/10.1167/iovs.07-0870

    Article  PubMed  Google Scholar 

  29. Jang JW, Kim MK, Lee YS, Lee JW, Kim DM, Song SH, Lee JY, Choi BY, Min B, Chi XZ, Bae SC (2017) RAC-LATS1/2 signaling regulates YAP activity by switching between the YAP-binding partners TEAD4 and RUNX3. Oncogene 36:999–1011. https://doi.org/10.1038/onc.2016.266

    Article  CAS  PubMed  Google Scholar 

  30. Kalucka J, de Rooij L, Goveia J, Rohlenova K, Dumas SJ, Meta E, Conchinha NV, Taverna F, Teuwen LA, Veys K, Garcia-Caballero M, Khan S, Geldhof V, Sokol L, Chen R, Treps L, Borri M, de Zeeuw P, Dubois C, Karakach TK, Falkenberg KD, Parys M, Yin X, Vinckier S, Du Y, Fenton RA, Schoonjans L, Dewerchin M, Eelen G, Thienpont B, Lin L, Bolund L, Li X, Luo Y, Carmeliet P (2020) Single-cell transcriptome atlas of murine endothelial cells. Cell 180(764–779):e720. https://doi.org/10.1016/j.cell.2020.01.015

    Article  CAS  Google Scholar 

  31. Krueger I, Gremer L, Mangels L, Klier M, Jurk K, Willbold D, Bock HH, Elvers M (2020) Reelin amplifies glycoprotein VI activation and AlphaIIb Beta3 integrin outside-in signaling via PLC gamma 2 and Rho GTPases. Arterioscler Thromb Vasc Biol 40:2391–2403. https://doi.org/10.1161/ATVBAHA.120.314902

    Article  CAS  PubMed  Google Scholar 

  32. Langfelder P, Horvath S (2008) WGCNA: an R package for weighted correlation network analysis. BMC Bioinform 9:559. https://doi.org/10.1186/1471-2105-9-559

    Article  CAS  Google Scholar 

  33. Leung C, Engineer A, Kim MY, Lu X, Feng Q (2021) Myocardium-specific deletion of rac1 causes ventricular noncompaction and outflow tract defects. J Cardiovasc Dev Dis. https://doi.org/10.3390/jcdd8030029

    Article  PubMed  PubMed Central  Google Scholar 

  34. Li Y, Feng J, Song S, Li H, Yang H, Zhou B, Li Y, Yue Z, Lian H, Liu L, Hu S, Nie Y (2020) gp130 controls cardiomyocyte proliferation and heart regeneration. Circulation 142:967–982. https://doi.org/10.1161/CIRCULATIONAHA.119.044484

    Article  CAS  PubMed  Google Scholar 

  35. Li Z, Yao F, Yu P, Li D, Zhang M, Mao L, Shen X, Ren Z, Wang L, Zhou B (2022) Postnatal state transition of cardiomyocyte as a primary step in heart maturation. Protein Cell 13:842–862. https://doi.org/10.1007/s13238-022-00908-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA, Liu JO, Pan D (2012) Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev 26:1300–1305. https://doi.org/10.1101/gad.192856.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu X, De la Cruz E, Gu X, Balint L, Oxendine-Burns M, Terrones T, Ma W, Kuo HH, Lantz C, Bansal T, Thorp E, Burridge P, Jakus Z, Herz J, Cleaver O, Torres M, Oliver G (2020) Lymphoangiocrine signals promote cardiac growth and repair. Nature 588:705–711. https://doi.org/10.1038/s41586-020-2998-x

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mahmoud AI, Kocabas F, Muralidhar SA, Kimura W, Koura AS, Thet S, Porrello ER, Sadek HA (2013) Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature 497:249–253. https://doi.org/10.1038/nature12054

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Meng Z, Moroishi T, Guan KL (2016) Mechanisms of Hippo pathway regulation. Genes Dev 30:1–17. https://doi.org/10.1101/gad.274027.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Morikawa Y, Zhang M, Heallen T, Leach J, Tao G, Xiao Y, Bai Y, Li W, Willerson JT, Martin JF (2015) Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice. Sci Signal 8:ra41. https://doi.org/10.1126/scisignal.2005781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nguyen NUN, Canseco DC, Xiao F, Nakada Y, Li S, Lam NT, Muralidhar SA, Savla JJ, Hill JA, Le V, Zidan KA, El-Feky HW, Wang Z, Ahmed MS, Hubbi ME, Menendez-Montes I, Moon J, Ali SR, Le V, Villalobos E, Mohamed MS, Elhelaly WM, Thet S, Anene-Nzelu CG, Tan WLW, Foo RS, Meng X, Kanchwala M, Xing C, Roy J, Cyert MS, Rothermel BA, Sadek HA (2020) A calcineurin-Hoxb13 axis regulates growth mode of mammalian cardiomyocytes. Nature 582:271–276. https://doi.org/10.1038/s41586-020-2228-6

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nimpf J, Schneider WJ (2000) From cholesterol transport to signal transduction: low density lipoprotein receptor, very low density lipoprotein receptor, and apolipoprotein E receptor-2. Biochim Biophys Acta 1529:287–298. https://doi.org/10.1016/s1388-1981(00)00155-4

    Article  CAS  PubMed  Google Scholar 

  43. Oganesian A, Armstrong LC, Migliorini MM, Strickland DK, Bornstein P (2008) Thrombospondins use the VLDL receptor and a nonapoptotic pathway to inhibit cell division in microvascular endothelial cells. Mol Biol Cell 19:563–571. https://doi.org/10.1091/mbc.e07-07-0649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Olson MF, Ashworth A, Hall A (1995) An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science 269:1270–1272. https://doi.org/10.1126/science.7652575

    Article  ADS  CAS  PubMed  Google Scholar 

  45. Payapilly A, Malliri A (2018) Compartmentalisation of RAC1 signalling. Curr Opin Cell Biol 54:50–56. https://doi.org/10.1016/j.ceb.2018.04.009

    Article  CAS  PubMed  Google Scholar 

  46. Peng X, He Q, Li G, Ma J, Zhong TP (2016) Rac1-PAK2 pathway is essential for zebrafish heart regeneration. Biochem Biophys Res Commun 472:637–642. https://doi.org/10.1016/j.bbrc.2016.03.011

    Article  CAS  PubMed  Google Scholar 

  47. Perman JC, Bostrom P, Lindbom M, Lidberg U, StAhlman M, Hagg D, Lindskog H, Scharin Tang M, Omerovic E, Mattsson Hulten L, Jeppsson A, Petursson P, Herlitz J, Olivecrona G, Strickland DK, Ekroos K, Olofsson SO, Boren J (2011) The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction. J Clin Invest 121:2625–2640. https://doi.org/10.1172/JCI43068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT, Salzberg SL (2015) StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol 33:290–295. https://doi.org/10.1038/nbt.3122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pianca N, Sacchi F, Umansky KB, Chirivì M, Iommarini L, Da Pra S, Papa V, Bongiovanni C, Miano C, Pontis F, Braga L, Tassinari R, Pantano E, Patnala RS, Mazzeschi M, Cenacchi G, Porcelli AM, Lauriola M, Ventura C, Giacca M, Rizzi R, Tzahor E, D’Uva G (2022) Glucocorticoid receptor antagonization propels endogenous cardiomyocyte proliferation and cardiac regeneration. Nat Cardiovasc Res 1:617–633. https://doi.org/10.1038/s44161-022-00090-0

    Article  Google Scholar 

  50. Poppe D, Tiede I, Fritz G, Becker C, Bartsch B, Wirtz S, Strand D, Tanaka S, Galle PR, Bustelo XR, Neurath MF (2006) Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins. J Immunol 176:640–651. https://doi.org/10.4049/jimmunol.176.1.640

    Article  CAS  PubMed  Google Scholar 

  51. Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA (2011) Transient regenerative potential of the neonatal mouse heart. Science 331:1078–1080. https://doi.org/10.1126/science.1200708

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, Grinsfelder D, Rothermel BA, Chen R, Garcia JA, Santos CX, Thet S, Mori E, Kinter MT, Rindler PM, Zacchigna S, Mukherjee S, Chen DJ, Mahmoud AI, Giacca M, Rabinovitch PS, Aroumougame A, Shah AM, Szweda LI, Sadek HA (2014) The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 157:565–579. https://doi.org/10.1016/j.cell.2014.03.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Reddy SS, Connor TE, Weeber EJ, Rebeck W (2011) Similarities and differences in structure, expression, and functions of VLDLR and ApoER2. Mol Neurodegener 6:30. https://doi.org/10.1186/1750-1326-6-30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rice DS, Curran T (2001) Role of the reelin signaling pathway in central nervous system development. Annu Rev Neurosci 24:1005–1039. https://doi.org/10.1146/annurev.neuro.24.1.1005

    Article  CAS  PubMed  Google Scholar 

  55. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70:401–410. https://doi.org/10.1016/0092-8674(92)90164-8

    Article  CAS  PubMed  Google Scholar 

  56. Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26:139–140. https://doi.org/10.1093/bioinformatics/btp616

    Article  CAS  PubMed  Google Scholar 

  57. Sadek H, Olson EN (2020) Toward the goal of human heart regeneration. Cell Stem Cell 26:7–16. https://doi.org/10.1016/j.stem.2019.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Saga Y, Miyagawa-Tomita S, Takagi A, Kitajima S, Miyazaki J, Inoue T (1999) MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube. Development 126:3437–3447

    Article  CAS  PubMed  Google Scholar 

  59. Sero JE, Bakal C (2017) Multiparametric analysis of cell shape demonstrates that beta-PIX directly couples YAP activation to extracellular matrix adhesion. Cell Syst 4(84–96):e86. https://doi.org/10.1016/j.cels.2016.11.015

    Article  CAS  Google Scholar 

  60. Shi Y, Bollam SR, White SM, Laughlin SZ, Graham GT, Wadhwa M, Chen H, Nguyen C, Vitte J, Giovannini M, Toretsky J, Yi C (2016) Rac1-Mediated DNA damage and inflammation promote Nf2 tumorigenesis but also limit cell-cycle progression. Dev Cell 39:452–465. https://doi.org/10.1016/j.devcel.2016.09.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Skelly DA, Squiers GT, McLellan MA, Bolisetty MT, Robson P, Rosenthal NA, Pinto AR (2018) Single-cell transcriptional profiling reveals cellular diversity and intercommunication in the mouse heart. Cell Rep 22:600–610. https://doi.org/10.1016/j.celrep.2017.12.072

    Article  CAS  PubMed  Google Scholar 

  62. Staniszewska I, Zaveri S, Del Valle L, Oliva I, Rothman VL, Croul SE, Roberts DD, Mosher DF, Tuszynski GP, Marcinkiewicz C (2007) Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis. Circ Res 100:1308–1316. https://doi.org/10.1161/01.RES.0000266662.98355.66

    Article  CAS  PubMed  Google Scholar 

  63. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550. https://doi.org/10.1073/pnas.0506580102

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sun L, Gao J, Dong X, Liu M, Li D, Shi X, Dong JT, Lu X, Liu C, Zhou J (2008) EB1 promotes Aurora-B kinase activity through blocking its inactivation by protein phosphatase 2A. Proc Natl Acad Sci U S A 105:7153–7158. https://doi.org/10.1073/pnas.0710018105

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  65. Tiebel O, Oka K, Robinson K, Sullivan M, Martinez J, Nakamuta M, Ishimura-Oka K, Chan L (1999) Mouse very low-density lipoprotein receptor (VLDLR): gene structure, tissue-specific expression and dietary and developmental regulation. Atherosclerosis 145:239–251. https://doi.org/10.1016/s0021-9150(99)00068-4

    Article  CAS  PubMed  Google Scholar 

  66. Torrini C, Cubero RJ, Dirkx E, Braga L, Ali H, Prosdocimo G, Gutierrez MI, Collesi C, Licastro D, Zentilin L, Mano M, Zacchigna S, Vendruscolo M, Marsili M, Samal A, Giacca M (2019) Common regulatory pathways mediate activity of MicroRNAs inducing cardiomyocyte proliferation. Cell Rep 27(2759–2771):e2755. https://doi.org/10.1016/j.celrep.2019.05.005

    Article  CAS  Google Scholar 

  67. Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, Hammer RE, Richardson JA, Herz J (1999) Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97:689–701. https://doi.org/10.1016/s0092-8674(00)80782-5

    Article  CAS  PubMed  Google Scholar 

  68. von Gise A, Lin Z, Schlegelmilch K, Honor LB, Pan GM, Buck JN, Ma Q, Ishiwata T, Zhou B, Camargo FD, Pu WT (2012) YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc Natl Acad Sci U S A 109:2394–2399. https://doi.org/10.1073/pnas.1116136109

    Article  ADS  Google Scholar 

  69. Wang J, Liu S, Heallen T, Martin JF (2018) The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration. Nat Rev Cardiol 15:672–684. https://doi.org/10.1038/s41569-018-0063-3

    Article  CAS  PubMed  Google Scholar 

  70. Wang S, Sorenson CM, Sheibani N (2012) Lack of thrombospondin 1 and exacerbation of choroidal neovascularization. Arch Ophthalmol 130:615–620. https://doi.org/10.1001/archopthalmol.2011.1892

    Article  PubMed  PubMed Central  Google Scholar 

  71. Wang W, Qiao Y, Li Z (2018) New insights into modes of GPCR activation. Trends Pharmacol Sci 39:367–386. https://doi.org/10.1016/j.tips.2018.01.001

    Article  CAS  PubMed  Google Scholar 

  72. Wang Y, Yao F, Wang L, Li Z, Ren Z, Li D, Zhang M, Han L, Wang SQ, Zhou B, Wang L (2020) Single-cell analysis of murine fibroblasts identifies neonatal to adult switching that regulates cardiomyocyte maturation. Nat Commun 11:2585. https://doi.org/10.1038/s41467-020-16204-w

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wei K, Serpooshan V, Hurtado C, Diez-Cunado M, Zhao M, Maruyama S, Zhu W, Fajardo G, Noseda M, Nakamura K, Tian X, Liu Q, Wang A, Matsuura Y, Bushway P, Cai W, Savchenko A, Mahmoudi M, Schneider MD, van den Hoff MJ, Butte MJ, Yang PC, Walsh K, Zhou B, Bernstein D, Mercola M, Ruiz-Lozano P (2015) Epicardial FSTL1 reconstitution regenerates the adult mammalian heart. Nature 525:479–485. https://doi.org/10.1038/nature15372

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xin M, Kim Y, Sutherland LB, Murakami M, Qi X, McAnally J, Porrello ER, Mahmoud AI, Tan W, Shelton JM, Richardson JA, Sadek HA, Bassel-Duby R, Olson EN (2013) Hippo pathway effector Yap promotes cardiac regeneration. Proc Natl Acad Sci U S A 110:13839–13844. https://doi.org/10.1073/pnas.1313192110

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  75. Yagyu H, Lutz EP, Kako Y, Marks S, Hu Y, Choi SY, Bensadoun A, Goldberg IJ (2002) Very low density lipoprotein (VLDL) receptor-deficient mice have reduced lipoprotein lipase activity. Possible causes of hypertriglyceridemia and reduced body mass with VLDL receptor deficiency. J Biol Chem 277:10037–10043. https://doi.org/10.1074/jbc.M109966200

    Article  CAS  PubMed  Google Scholar 

  76. Zhang H, Pei L, Ouyang Z, Wang H, Chen X, Jiang K, Huang S, Jiang R, Xiang Y, Wei K (2022) AP-1 activation mediates post-natal cardiomyocyte maturation. Cardiovasc Res. https://doi.org/10.1093/cvr/cvac088

    Article  PubMed  PubMed Central  Google Scholar 

  77. Zhang J, Ouyang Z, Xia L, Wang Q, Zheng F, Xu K, Xing Y, Wei K, Shi S, Li C, Yang J (2023) Dynamic chromatin landscape encodes programs for perinatal transition of cardiomyocytes. Cell Death Discov 9:11. https://doi.org/10.1038/s41420-023-01322-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was funded by the Key Research and Development Program, Ministry of Science and Technology of China (2018YFA0800104, 2017YFA0105601), National Natural Science Foundation of China (31771613, 32070823, 92168205), and Fundamental Research Funds for the Central Universities (22120200411). The authors thank the Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai, and the Frontier Science Research Center for Stem Cells, Ministry of Education for their support. Fig. 7a, f, Fig. 8a, d and Fig. 9 were created with BioRender.com.

Author information

Author notes

  1. Lijuan Pei and Zhaohui Ouyang have contributed equally to this work.

Authors and Affiliations

  1. School of Life Sciences and Technology, Institute for Regenerative Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Shanghai East Hospital, Shanghai Institute of Stem Cell Research and Clinical Translation, Tongji University, 1239 Siping Road, Shanghai, 200092, China

    Lijuan Pei, Zhaohui Ouyang, Hongjie Zhang, Shiqi Huang, Rui Jiang, Mengying Feng, Min Yuan, Haocun Wang, Su Yao, Shuyue Shi, Zhao Yu & Ke Wei

  2. Institute for Regenerative Medicine, School of Life Sciences and Technology, Shanghai East Hospital, Tongji University, Shanghai, 200092, China

    Bilin Liu & Guohua Gong

  3. Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China

    Yansong Tang & Dachun Xu

Authors
  1. Lijuan Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhaohui Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongjie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shiqi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rui Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bilin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yansong Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mengying Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Min Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Haocun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Su Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shuyue Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Zhao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Dachun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Guohua Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ke Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LP and KW conceived the project, LP and ZO performed in vitro and in vivo experiments, HZ performed bioinformatic analysis, ZO, SH, RJ and ZY performed NRVC experiments, YT, MF, MY, and HW performed experiments on mice, BL performed myocardial infarction experiments, MF, MY, SY and SS performed experiments in hESCs and hiPSCs, DX, GG and KW supervised all experiments, and LP, ZO and KW wrote the manuscript.

Corresponding author

Correspondence to Ke Wei.

Ethics declarations

Conflict of interest

The authors declare no conflict of interests.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pei, L., Ouyang, Z., Zhang, H. et al. Thrombospondin 1 and Reelin act through Vldlr to regulate cardiac growth and repair. Basic Res Cardiol 119, 169–192 (2024). https://doi.org/10.1007/s00395-023-01021-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-023-01021-1

Keywords

Search

Navigation