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Cell Barcoding Reveals Lineage-dependent Outcomes in hiPSC Cardiac Differentiation
Sogu Sohn1, Daylin Morgan1, Cody Callahan1
1Department of Biomedical Engineering, The University of Texas at Austin.
Insights
Clinical scalability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be improved by controlling clonal heterogeneity. Tracking hiPSC lineages revealed that specific lineages preferentially differentiate into cardiomyocytes, impacting outcomes.
Area of Science:
- Stem Cell Biology
- Cardiovascular Research
- Biotechnology
Background:
- Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) show promise for cardiovascular disease treatment.
- Clinical translation is hindered by poor scalability and significant heterogeneity in hiPSC-CM differentiation.
- Controlling hiPSC clonal heterogeneity is a potential strategy to enhance scalability.
Purpose of the Study:
- To investigate the phenomenon of "fate priming" in hiPSC cardiac differentiation.
- To determine if clonal lineage identity influences differentiation outcomes.
- To assess the impact of clonal heterogeneity on hiPSC-CM production.
Main Methods:
- Utilized the ClonMapper cell barcoding platform for labeling, tracking, and isolating distinct hiPSC lineages.
- Compared cardiac differentiation outcomes between single-clone hiPSC populations and heterogeneous multi-clone populations.
- Analyzed lineage-specific differentiation preferences towards cardiomyocytes or non-cardiomyocytes.
Main Results:
- Identified specific hiPSC lineages exhibiting preferential differentiation into either hiPSC-CMs or non-cardiomyocytes.
- Demonstrated significant differences in cardiac differentiation outcomes between isolated single-clone populations and heterogeneous populations.
- Confirmed the influence of lineage identity on hiPSC cardiac differentiation.
Conclusions:
- hiPSC clonal heterogeneity significantly impacts cardiac differentiation efficiency and outcomes.
- The concept of "fate priming" is relevant to hiPSC cardiac differentiation.
- Targeting and controlling hiPSC lineage identity can improve the clinical scalability of hiPSC-CMs.
Abstract:
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have potential applications in treating cardiovascular disease but are currently limited in their clinical translation. A primary limitation is the poor clinical scalability of hiPSC-CMs, with the heterogeneity of hiPSC cardiac differentiation significantly contributing to this limitation. We hypothesize that clinical scalability can be improved by tracking and controlling hiPSC clonal heterogeneity, a variable often overlooked in current differentiation approaches. "Fate priming", wherein clonal lineage identity determines differentiation fate, has been demonstrated in other stem cell differentiation pathways. We investigated fate priming in hiPSC cardiac differentiation using the ClonMapper cell barcoding platform to label, track, and isolate distinct hiPSC lineages from the same cell line. We show that certain hiPSC lineages preferentially differentiate into hiPSC-CMs or non-CMs. After isolating lineages with apparent fate priming, we found significant differences in cardiac differentiation outcomes between these single-clone populations and heterogeneous, multi-clone hiPSC populations. These findings indicate that lineage identity influences hiPSC cardiac differentiation outcomes.
