Developmental lineage of human pluripotent stem cell-derived cardiac fibroblasts affects their functional phenotype

Martha E. Floy, Sophie E. Givens, Oriane B. Matthys, Taylor D. Mateyka, Charles M. Kerr, Alexandra B. Steinberg, Ana C. Silva, Jianhua Zhang, Ying Mei, Brenda M. Ogle, Todd C. McDevitt, Timothy J. Kamp, Sean P. Palecek

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiac fibroblasts (CFBs) support heart function by secreting extracellular matrix (ECM) and paracrine factors, respond to stress associated with injury and disease, and therefore are an increasingly important therapeutic target. We describe how developmental lineage of human pluripotent stem cell-derived CFBs, epicardial (EpiC-FB), and second heart field (SHF-FB) impacts transcriptional and functional properties. Both EpiC-FBs and SHF-FBs exhibited CFB transcriptional programs and improved calcium handling in human pluripotent stem cell-derived cardiac tissues. We identified differences including in composition of ECM synthesized, secretion of growth and differentiation factors, and myofibroblast activation potential, with EpiC-FBs exhibiting higher stress-induced activation potential akin to myofibroblasts and SHF-FBs demonstrating higher calcification and mineralization potential. These phenotypic differences suggest that EpiC-FBs have utility in modeling fibrotic diseases while SHF-FBs are a promising source of cells for regenerative therapies. This work directly contrasts regional and developmental specificity of CFBs and informs CFB in vitro model selection.

Original languageEnglish (US)
Article numbere21799
JournalFASEB Journal
Volume35
Issue number9
DOIs
StatePublished - Sep 2021

Bibliographical note

Funding Information:
MEF, OBM, TDM, ABS, JZ, TCM, TJK, and SPP would like to acknowledge support from the NSF Engineering Research Center for Cell Manufacturing Technologies (CMaT; NSF EEC‐1648035), NSF grant CBET‐1066311, and NIH grant R01 EB007534. OBM was a National Science Foundation Graduate Research Fellow (1650113) and OBM, ACS, and TCM acknowledge funding support from the California Institute for Regenerative Medicine (LA1‐08015). CMK was funded by NIH T32 HL007260 and NIH F31 HL154665. YM would like to acknowledge the support from NIH (R01 HL133308). BMO would like to acknowledge support from NIH (R01 HL137204). SEG would like to acknowledge support from the National Science Foundation Graduate Research Fellowship Program (2019272038).

Funding Information:
The authors would like to thank Benjamin Gastfriend and Koji Foreman for their assistance in designing figures and statistical analysis. The authors thank the University of Wisconsin Biotechnology Center DNA Sequencing Facility for providing RNA sequencing facilities and services. The authors also thank the Gladstone Institutes Histology and Light Microscopy Core for paraffin processing of microtissue samples and the Gladstone Stem Cell Core (Roddenberry Stem Cell Foundation) and Ronald Manlapaz for stem cell culture and cardiomyocyte differentiation support. MEF, OBM, TDM, ABS, JZ, TCM, TJK, and SPP would like to acknowledge support from the NSF Engineering Research Center for Cell Manufacturing Technologies (CMaT; NSF EEC-1648035), NSF grant CBET-1066311, and NIH grant R01 EB007534. OBM was a National Science Foundation Graduate Research Fellow (1650113) and OBM, ACS, and TCM acknowledge funding support from the California Institute for Regenerative Medicine (LA1-08015). CMK was funded by NIH T32 HL007260 and NIH F31 HL154665. YM would like to acknowledge the support from NIH (R01 HL133308). BMO would like to acknowledge support from NIH (R01 HL137204). SEG would like to acknowledge support from the National Science Foundation Graduate Research Fellowship Program (2019272038).

Publisher Copyright:
© 2021 Federation of American Societies for Experimental Biology.

Keywords

  • cardiac
  • fibroblast
  • pluripotent stem cell

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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