Academic Journal
Cellular Reprogramming by PHF7 Enhances Cardiac Function Following Myocardial Infarction.
| Title: | Cellular Reprogramming by PHF7 Enhances Cardiac Function Following Myocardial Infarction. |
|---|---|
| Authors: | Bann GG; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (G.G.B., M.D.S., W.T., S.B., P.C., N.L., R.B.-D., E.N.O.).; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX (G.G.B.)., Dos Santos M; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (G.G.B., M.D.S., W.T., S.B., P.C., N.L., R.B.-D., E.N.O.)., Chen K; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX (K.C., L.X.)., Tan W; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (G.G.B., M.D.S., W.T., S.B., P.C., N.L., R.B.-D., E.N.O.)., Bezprozvannaya S; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (G.G.B., M.D.S., W.T., S.B., P.C., N.L., R.B.-D., E.N.O.)., Gan P, Xu L; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX (K.C., L.X.)., Liu N; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (G.G.B., M.D.S., W.T., S.B., P.C., N.L., R.B.-D., E.N.O.)., Bassel-Duby R; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (G.G.B., M.D.S., W.T., S.B., P.C., N.L., R.B.-D., E.N.O.)., Olson EN; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (G.G.B., M.D.S., W.T., S.B., P.C., N.L., R.B.-D., E.N.O.). |
| Source: | Circulation [Circulation] 2025 Sep 02; Vol. 152 (9), pp. 616-629. Date of Electronic Publication: 2025 Jul 09. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0147763 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4539 (Electronic) Linking ISSN: 00097322 NLM ISO Abbreviation: Circulation Subsets: MEDLINE |
| Imprint Name(s): | Publication: Hagerstown, MD : Lippincott Williams & Wilkins Original Publication: [Dallas, Tex., etc., American Heart Association, etc.] |
| MeSH Terms: | Myocardial Infarction*/metabolism , Myocardial Infarction*/genetics , Myocardial Infarction*/pathology , Myocardial Infarction*/physiopathology , Myocardial Infarction*/therapy , Myocytes, Cardiac*/metabolism , Myocytes, Cardiac*/pathology , Transcription Factors*/genetics , Transcription Factors*/metabolism , Cellular Reprogramming*, Fibroblasts/metabolism ; MEF2 Transcription Factors/genetics ; MEF2 Transcription Factors/metabolism ; Animals ; Mice ; Humans ; Disease Models, Animal ; Mice, Inbred C57BL ; Cells, Cultured ; Male ; T-Box Domain Proteins |
| Abstract: | Background: Direct reprogramming of fibroblasts to cardiomyocytes is a potentially curative strategy for ischemic heart disease. However, current reprogramming strategies require excessive factors due to epigenetic barriers of adult mouse and human fibroblasts. Recently, we identified the epigenetic factor PHF7 from a screen of gene-regulatory factors as the most potent activator of adult fibroblast-to-cardiomyocyte reprogramming in vitro. Methods: Through in vitro assays coupled with genome-wide studies, we interrogated the ability of PHF7 to induce reprogramming events with minimal reprogramming factors. Using in vivo murine models of myocardial infarction and intramyocardial reprogramming factor delivery coupled with genetic fibroblast lineage tracing, we delivered retroviral PHF7 cocktails to the murine heart and interrogated reprogramming events as well as the acute and chronic functional impact of these cocktails. Deployment of 10X multiomics in vivo generated a combinatorial single-nucleus transcriptomic and epigenomic atlas of PHF7 reprogramming in the infarcted heart. Results: Genome-wide in vitro transcriptomic analyses revealed that addition of PHF7 to Tbx5 or Mef2c and Tbx5 in fibroblasts induced global reprogramming through upregulation of unique cardiac transcriptomes. Further, PHF7 itself upregulated cardiac master regulators when overexpressed in dermal fibroblasts. Delivery of PHF7 cocktails to the infarcted murine heart induced in vivo reprogramming events and improved cardiac function and remodeling in both acute and chronic heart failure. When delivered as a single factor to the infarcted heart, PHF7 improved survival, function, and fibrosis up to 16 weeks after injury. Genetic lineage tracing analyses revealed that PHF7 induced bona fide fibroblast-to-cardiomyocyte reprogramming events in vivo. Comprehensive multiomics of PHF7 cocktails in the infarcted heart exposed the impact of PHF7 on chromatin structure, generating population-level shifts in nonmyocyte and cardiomyocyte cellular identity. Conclusions: Here, we report the ability of a single epigenetic factor, PHF7, to induce reprogramming and improve cardiac function in the mouse heart following myocardial infarction. Together, these data support the premise that a single factor, when deployed into the infarcted mouse heart, can induce reprogramming events and recover function in the ischemic heart. |
| Competing Interests: | Dr Olson is a cofounder and member of the scientific advisory board of Tenaya Therapeutics and holds equity in the company. Dr Olson is a consultant for Vertex Pharmaceuticals and Cardurion Pharmaceuticals. Drs Bann and Olson are inventors on US patent application 18/706 525 based on international patent application PCT/US2022/078854 entitled “Reprogramming of Adult Cardiac Fibroblasts Into Cardiomyocytes Using PHF7” in the name of the board of regents of the University of Texas System. |
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| Grant Information: | R01 HL077439 United States HL NHLBI NIH HHS; R01 HL083371 United States HL NHLBI NIH HHS; R01 HL138426 United States HL NHLBI NIH HHS; R01 HL157281 United States HL NHLBI NIH HHS; R01 HL130253 United States HL NHLBI NIH HHS; K08 HL172012 United States HL NHLBI NIH HHS; U54 HD087351 United States HD NICHD NIH HHS; P50 HD087351 United States HD NICHD NIH HHS; F32 HL160116 United States HL NHLBI NIH HHS |
| Contributed Indexing: | Keywords: cellular reprogramming; direct cell reprogramming techniques; epigenomics; heart failure; myocardial infarction |
| Substance Nomenclature: | 0 (Transcription Factors) 0 (MEF2 Transcription Factors) 0 (T-box transcription factor 5) 0 (T-Box Domain Proteins) |
| Entry Date(s): | Date Created: 20250709 Date Completed: 20250902 Latest Revision: 20260425 |
| Update Code: | 20260425 |
| PubMed Central ID: | PMC12327843 |
| DOI: | 10.1161/CIRCULATIONAHA.124.072733 |
| PMID: | 40631661 |
| Database: | MEDLINE |
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