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Peer-reviewedCC BY 4.0Frontiers in Cardiovascular Medicine

hiPSC-derived new approach methodology (NAM) recapitulates hallmarks of atrial fibrillation

  • Paul Kozlowski1,2
  • Kalai Mangai Muthukumarasamy2
  • Tiago William Buranello3
  • Sung Jo3
  • Amrish Deshmukh2
  • Andre Monteiro da Rocha2,3
  • Hakan Oral2,3
  1. 1Medical School, University of Michigan
  2. 2Internal Medicine – Cardiovascular Medicine, University of Michigan
  3. 3Frankel Cardiovascular Center Cell Regeneration Core Laboratory, University of Michigan
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Abstract

Background and aim: Human in vitro models for atrial fibrillation (AF) remain limited in reproducing disease-specific remodeling. We leveraged a human-induced pluripotent stem cell-derived atrial cardiomyocyte (hiPSC-aCM) model, which was co-cultured with human atrial cardiac fibroblasts (haCFs) and subjected to an intermittent tachypacing protocol (ITPP) to mimic AF-associated phenotypes.

Materials and methods: Human iPSC-derived atrial cardiomyocytes (hiPSC-aCMs) were differentiated, purified, matured, and cultured alone or co-cultured with human atrial cardiac fibroblasts at defined seeding ratios (e.g., 90/10 or 70/30 hiPSC-aCM/haCF). Cultures were subjected to 7 days of intermittent tachypacing using electrical field stimulation. Functional electrophysiology and calcium handling were assessed by high-throughput optical mapping, arrhythmia inducibility testing, and genetically encoded or chemical calcium indicators. Structural and molecular remodeling were evaluated by immunocytochemistry, qPCR, and Western blot analysis.

Results: ITPP increased spontaneous action potential (AP) frequency and shortened AP duration at 80% repolarization (APD 80% ), while reducing calcium transient (CaT) upstroke slope and amplitude. Co-cultures at a 70/30 hiPSC-aCM/haCF ratio exhibited marked structural remodeling, with a >100-fold increase in Collagen III expression ( P < 0.0001), decreased excitability (ΔHz = –61 ± 6%, P < 0.0001), prolonged APD 80% (Δ = +130 ± 10%, P < 0.0001), increased triangulation (ΔAPD Tri = +143 ± 13%, P < 0.0001), reduced upstroke slope (Δ = –66 ± 6%, P < 0.0001), conduction block (Δ = –52 ± 18%, P = 0.026), and impaired Ca ² ⁺ handling (upstroke slope Δ = –50 ± 8%, P < 0.0001; ΔdF/F0 = –34 ± 9%, P = 0.0003). Applying ITPP to the 70/30 co-culture induced AF-like remodeling, with increased spontaneous activity (ΔHz = +25 ± 8%, P = 0.02), shortened APD 80% (Δ = –16 ± 6%, P = 0.01), and reduced conduction velocity (ΔCV 100/0 vs. 70/30 = –27 ± 15%, P = 0.0005). Mechanistically, ITPP led to downregulation of phospholamban (PLN) and altered PLN-SERCA2a balance, along with upregulation of TGFB1 and natriuretic peptides, reflecting calcium-handling dysfunction and pro-fibrotic signaling.

Conclusion: Together, these findings establish a human-relevant platform in 2D culture that recapitulates key AF-associated structural and electrophysiological remodeling for mechanistic studies and therapeutic screening.

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Cite

BibTeXRIS
BibTeX
@article{kozlowski2026hipscderived,
  title = {{hiPSC-derived new approach methodology (NAM) recapitulates hallmarks of atrial fibrillation}},
  author = {Paul Kozlowski and Kalai Mangai Muthukumarasamy and Tiago William Buranello and Sung Jo and Amrish Deshmukh and Andre Monteiro da Rocha and Hakan Oral},
  journal = {Frontiers in Cardiovascular Medicine},
  year = {2026},
  month = oct,
  doi = {10.3389/fcvm.2026.1814075},
  url = {https://www.frontiersin.org/articles/10.3389/fcvm.2026.1814075/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - hiPSC-derived new approach methodology (NAM) recapitulates hallmarks of atrial fibrillation
AU  - Paul Kozlowski
AU  - Kalai Mangai Muthukumarasamy
AU  - Tiago William Buranello
AU  - Sung Jo
AU  - Amrish Deshmukh
AU  - Andre Monteiro da Rocha
AU  - Hakan Oral
PY  - 2026
DA  - 2026/10/20
JO  - Frontiers in Cardiovascular Medicine
DO  - 10.3389/fcvm.2026.1814075
UR  - https://www.frontiersin.org/articles/10.3389/fcvm.2026.1814075/full
AB  - Background and aim: Human in vitro models for atrial fibrillation (AF) remain limited in reproducing disease-specific remodeling. We leveraged a human-induced pluripotent stem cell-derived atrial cardiomyocyte (hiPSC-aCM) model, which was co-cultured with human atrial cardiac fibroblasts (haCFs) and subjected to an intermittent tachypacing protocol (ITPP) to mimic AF-associated phenotypes.  Materials and methods: Human iPSC-derived atrial cardiomyocytes (hiPSC-aCMs) were differentiated, purified, matured, and cultured alone or co-cultured with human atrial cardiac fibroblasts at defined seeding ratios (e.g., 90/10 or 70/30 hiPSC-aCM/haCF). Cultures were subjected to 7 days of intermittent tachypacing using electrical field stimulation. Functional electrophysiology and calcium handling were assessed by high-throughput optical mapping, arrhythmia inducibility testing, and genetically encoded or chemical calcium indicators. Structural and molecular remodeling were evaluated by immunocytochemistry, qPCR, and Western blot analysis.  Results: ITPP increased spontaneous action potential (AP) frequency and shortened AP duration at 80% repolarization (APD 80% ), while reducing calcium transient (CaT) upstroke slope and amplitude. Co-cultures at a 70/30 hiPSC-aCM/haCF ratio exhibited marked structural remodeling, with a >100-fold increase in Collagen III expression ( P < 0.0001), decreased excitability (ΔHz = –61 ± 6%, P < 0.0001), prolonged APD 80% (Δ = +130 ± 10%, P < 0.0001), increased triangulation (ΔAPD Tri = +143 ± 13%, P < 0.0001), reduced upstroke slope (Δ = –66 ± 6%, P < 0.0001), conduction block (Δ = –52 ± 18%, P = 0.026), and impaired Ca ² ⁺ handling (upstroke slope Δ = –50 ± 8%, P < 0.0001; ΔdF/F0 = –34 ± 9%, P = 0.0003). Applying ITPP to the 70/30 co-culture induced AF-like remodeling, with increased spontaneous activity (ΔHz = +25 ± 8%, P = 0.02), shortened APD 80% (Δ = –16 ± 6%, P = 0.01), and reduced conduction velocity (ΔCV 100/0 vs. 70/30 = –27 ± 15%, P = 0.0005). Mechanistically, ITPP led to downregulation of phospholamban (PLN) and altered PLN-SERCA2a balance, along with upregulation of TGFB1 and natriuretic peptides, reflecting calcium-handling dysfunction and pro-fibrotic signaling.  Conclusion: Together, these findings establish a human-relevant platform in 2D culture that recapitulates key AF-associated structural and electrophysiological remodeling for mechanistic studies and therapeutic screening.
SN  - 2297-055X
ER  -