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Integrated multi-omic characterization of congenital heart disease

  • Matthew C. Hill
  • , Zachary A. Kadow
  • , Hali Long
  • , Yuka Morikawa
  • , Thomas J. Martin
  • , Emma J. Birks
  • , Kenneth S. Campbell
  • , Jeanne Nerbonne
  • , Kory Lavine
  • , Lalita Wadhwa
  • , Jun Wang
  • , Diwakar Turaga
  • , Iki Adachi
  • , James F. Martin

Producción científica: Article › revisión exhaustiva

102 Citas (Scopus)

Resumen

The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes1. Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1. Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer2. Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD.

Idioma originalEnglish
Páginas (desde-hasta)181-191
Número de páginas11
PublicaciónNature
Volumen608
N.º7921
DOI
EstadoPublished - ago 4 2022

Nota bibliográfica

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Financiación

This work was supported by the Department of Defense (CDMRP) W81XWH-17-1-0418 (J.F.M.); National Institutes of Health (1F31HL156681-01 (H.L.), F30HL145908 (Z.A.K.), 5T32HL007208-42 (M.C.H.), R56 HL142704 and R01HL142704 (J.W.), and R01HL 127717, R01HL 130804 and R01HL 118761 (J.F.M.); the Vivian L. Smith Foundation (J.F.M.); Baylor Research Advocates for Student Scientists and Baylor College of Medicine Medical Scientist Training Program (Z.A.K.); the LeDucq Foundation’s Transatlantic Networks of Excellence in Cardiovascular Research (14CVD01: Defining the Genomic Topology of Atrial Fibrillation), the MacDonald Research Fund Award (16RDM001), and a grant from the Saving Tiny Hearts Society (J.F.M.); and NIH HL149164, HL148785 and University of Kentucky Myocardial Recovery Alliance (E.J.B. and K.S.C.). The TCBR is supported by: Children’s Discovery Institute of Washington University and St Louis Children’s Hospital (PM-LI-2019-829) (J.N. and K.L.), the Baylor College of Medicine Pathology and Histology Core and the BCM Breast Cancer Core. This project was supported by the Optical Imaging and Vital Microscopy (OiVM) core at BCM. This research was performed in the Flow Cytometry and Cellular Imaging Core Facility, which is supported in part by the National Institutes of Health through M. D. Anderson's Cancer Center Support Grant CA016672, the NCI’s Research Specialist 1 R50 CA243707-01A1, and a Shared Instrumentation Award from the Cancer Prevention Research Institution of Texas (CPRIT), RP121010. This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (CA125123 and RR024574) and the assistance of J. M. Sederstrom. This project was supported in part by the Genomic and RNA Profiling Core at Baylor College of Medicine with funding from the NIH S10 grant (1S10OD023469). We acknowledge the Gill Cardiovascular Biorepository at the University of Kentucky for providing paediatric control myocardium samples. N. Stancel provided editorial support. Artwork for some figures was generated with BioRender.com. This work was supported by the Department of Defense (CDMRP) W81XWH-17-1-0418 (J.F.M.); National Institutes of Health (1F31HL156681-01 (H.L.), F30HL145908 (Z.A.K.), 5T32HL007208-42 (M.C.H.), R56 HL142704 and R01HL142704 (J.W.), and R01HL 127717, R01HL 130804 and R01HL 118761 (J.F.M.); the Vivian L. Smith Foundation (J.F.M.); Baylor Research Advocates for Student Scientists and Baylor College of Medicine Medical Scientist Training Program (Z.A.K.); the LeDucq Foundation’s Transatlantic Networks of Excellence in Cardiovascular Research (14CVD01: Defining the Genomic Topology of Atrial Fibrillation), the MacDonald Research Fund Award (16RDM001), and a grant from the Saving Tiny Hearts Society (J.F.M.); and NIH HL149164, HL148785 and University of Kentucky Myocardial Recovery Alliance (E.J.B. and K.S.C.). The TCBR is supported by: Children’s Discovery Institute of Washington University and St Louis Children’s Hospital (PM-LI-2019-829) (J.N. and K.L.), the Baylor College of Medicine Pathology and Histology Core and the BCM Breast Cancer Core. This project was supported by the Optical Imaging and Vital Microscopy (OiVM) core at BCM. This research was performed in the Flow Cytometry and Cellular Imaging Core Facility, which is supported in part by the National Institutes of Health through M. D. Anderson's Cancer Center Support Grant CA016672, the NCI’s Research Specialist 1 R50 CA243707-01A1, and a Shared Instrumentation Award from the Cancer Prevention Research Institution of Texas (CPRIT), RP121010. This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (CA125123 and RR024574) and the assistance of J. M. Sederstrom. This project was supported in part by the Genomic and RNA Profiling Core at Baylor College of Medicine with funding from the NIH S10 grant (1S10OD023469). We acknowledge the Gill Cardiovascular Biorepository at the University of Kentucky for providing paediatric control myocardium samples. N. Stancel provided editorial support. Artwork for some figures was generated with BioRender.com.

FinanciadoresNúmero del financiador
Baylor Research Advocates
Children’s Discovery Institute of Washington University
University of Kentucky Myocardial Recovery Alliance
National Institutes of Health (NIH)HL148785, 5T32HL007208-42, R01HL 118761, 1F31HL156681-01, F30HL145908, R01HL142704, HL149164, R01HL 127717
U.S. Department of Defense
National Heart, Lung, and Blood Institute (NHLBI)R01HL130804
National Childhood Cancer Registry – National Cancer Institute1 R50 CA243707-01A1
Congressionally Directed Medical Research ProgramsW81XWH-17-1-0418
Cancer Prevention and Research Institute of TexasRR024574, 1S10OD023469, CA125123, RP121010, CPRIT-RP180672
University of Kentucky
Baylor College of MedicineCA016672
Saving Tiny Hearts Society
St. Louis Children's HospitalPM-LI-2019-829
Vivian L. Smith Foundation
Fondation Leducq16RDM001

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