Lee Lab

Rich Lee, M.D.

Rich Lee, M.D.

Professor of Stem Cell and Regenerative Biology at Harvard University
Professor of Medicine, Brigham and Women's Hospital
Principal Faculty, Harvard Stem Cell Institute

Richard T. Lee is Professor of Stem Cell and Regenerative Biology at Harvard University and Professor of Medicine at Harvard Medical School. Dr. Lee is a...

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Vujic, A., et al., 2018. Exercise induces new cardiomyocyte generation in the adult mammalian heart. Nature Communications , 9 (1659). Publisher's VersionAbstract
Loss of cardiomyocytes is a major cause of heart failure, and while the adult heart has a limited capacity for cardiomyogenesis, little is known about what regulates this ability or whether it can be effectively harnessed. Here we show that 8 weeks of running exercise increase birth of new cardiomyocytes in adult mice (~4.6-fold). New cardiomyocytes are identified based on incorporation of 15N-thymidine by multi-isotope imaging mass spectrometry (MIMS) and on being mononucleate/diploid. Furthermore, we demonstrate that exercise after myocardial infarction induces a robust cardiomyogenic response in an extended border zone of the infarcted area. Inhibition of miR-222, a microRNA increased by exercise in both animal models and humans, completely blocks the cardiomyogenic exercise response. These findings demonstrate that cardiomyogenesis can be activated by exercise in the normal and injured adult mouse heart and suggest that stimulation of endogenous cardiomyocyte generation could contribute to the benefits of exercise.
Natarajan, N., et al., 2018. Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration. Circulation , 137 (5). Publisher's VersionAbstract

Background—Defining conserved molecular pathways in animal models of successful cardiac regeneration could yield insight into why adult mammals have inadequate cardiac regeneration after injury. Insight into the transcriptomic landscape of early cardiac regeneration from model organisms will shed light on evolutionarily conserved pathways in successful cardiac regeneration.

Methods—Here we describe a cross-species transcriptomic screen in three model organisms for cardiac regeneration -axolotl, neonatal mice and zebrafish. Apical resection to remove ~10 - 20% of ventricular mass was carried out in these model organisms. RNA-seq analysis was performed on the hearts harvested at three time points - 12, 24 and 48 hours post-resection. Sham surgery was used as internal control.

Results—Genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors (activated by complement components, part of the innate immune system) were found to be highly upregulated in all three species. This approach revealed induction of gene expression for Complement 5a receptor1 (C5aR1) in the regenerating hearts of zebrafish, axolotls and mice. Inhibition of C5aR1 significantly attenuated the cardiomyocyte proliferative response to heart injury in all three species. Furthermore, following left ventricular apical resection, the cardiomyocyte proliferative response was abolished in mice with genetic deletion of C5aR1.

Conclusions—These data reveal that activation of C5aR1 mediates an evolutionarily conserved response that promotes cardiomyocyte proliferation following cardiac injury and identify complement pathway activation as a common pathway of successful heart regeneration.

Walker, R.G., et al., 2017. Structural basis for potency differences between GDF8 and GDF11. BMC Biol , 15 (1) , pp. 19.Abstract

BACKGROUND: Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. RESULTS: Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. CONCLUSIONS: These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined.

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