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Stem cells transform into a cardiac phenotype with remodeling of the nuclear transport machinery

Nature Clinical Practice Cardiovascular Medicine volume 4, pages S68–S76 (2007)Cite this article

Abstract

Nuclear transport of transcription factors is a critical step in stem cell commitment to a tissue-specific lineage. While it is recognized that nuclear pores are gatekeepers of nucleocytoplasmic exchange, it is unknown how the nuclear transport machinery becomes competent to support genetic reprogramming and cell differentiation. Here, we report the dynamics of nuclear transport factor expression and nuclear pore microanatomy during cardiac differentiation of embryonic stem cells. Cardiac progeny derived from pluripotent stem cells displayed a distinct proteomic profile characterized by the emergence of cardiac-specific proteins. This profile correlated with the nuclear translocation of cardiac transcription factors. The nuclear transport genes, including nucleoporins, importins, exportins, transportins, and Ran-related factors, were globally downregulated at the genomic level, streamlining the differentiation program underlying stem cell-derived cardiogenesis. Establishment of the cardiac molecular phenotype was associated with an increased density of nuclear pores spanning the nuclear envelope. At nanoscale resolution, individual nuclear pores exhibited conformational changes resulting in the expansion of the pore diameter and an augmented probability of conduit occupancy. Thus, embryonic stem cells undergo adaptive remodeling of the nuclear transport infrastructure associated with nuclear translocation of cardiac transcription factors and execution of the cardiogenic program, underscoring the plasticity of the nucleocytoplasmic trafficking machinery in accommodating differentiation requirements.

Key Points

  • Embryonic stem cell differentiation into cardiac progeny is associated with remodeling of the nuclear transport machinery

  • Securing the cardiac phenotype from stem cells through nuclear translocation of cardiac transcription factors correlates with acquisition of a distinct proteome

  • Genetic reprogramming by streamlined transcription of nuclear transport genes fingerprints stem cell cardiac commitment

  • Conformational remodeling of the nuclear transport conduit provides the structural substrate for the establishment of the cardiac phenotype

  • Adaptation within the nuclear transport machinery underlies cardiac differentiation and exposes targets to expedite cardiogenesis

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Figure 1: Nuclear translocation of cardiac transcription factors drives cardiac stem cell differentiation
Figure 2: Conformational changes in nuclear pores and cardiac stem cell differentiation
Figure 3: Streamlining of nuclear transport-related genes in cardiac differentiation

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Acknowledgements

This work was supported by the National Institutes of Health (NIH), American Heart Association (AHA), Marriott Heart Disease Research Program, Marriott Foundation, Ted Nash Long Life Foundation, Ralph Wilson Medical Research Foundation, Asper Foundation, Heart and Stroke Foundation of Canada, and Mayo Clinic.

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Authors and Affiliations

  1. Division of Cardiovascular Diseases, Departments of Medicine, C Perez-Terzic is Assistant Professor of Physical Medicine and Rehabilitation and Associate Director Cardiovascular Rehabilitation, RS Faustino is an Asper Foundation Fellow, BJ Boorsma is a biomedical sciences trainee, DK Arrell is a Heart and Stroke Foundation of Canada Fellow, NJ Niederländer is a Ted Nash Foundation Fellow, A Behfar is a Clinician Investigator Scholar, and A Terzic is Marriott Family Professor of Cardiovascular Research and Professor of Medicine and Pharmacology, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.,

    Carmen Perez-Terzic, Randolph S Faustino, Brian J Boorsma, D Kent Arrell, Nicolas J Niederländer, Atta Behfar & Andre Terzic

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  1. Carmen Perez-Terzic
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Correspondence to Andre Terzic.

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Perez-Terzic, C., Faustino, R., Boorsma, B. et al. Stem cells transform into a cardiac phenotype with remodeling of the nuclear transport machinery. Nat Rev Cardiol 4 (Suppl 1), S68–S76 (2007). https://doi.org/10.1038/ncpcardio0763

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