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New Mapping Study in the Mouse Heart Finds No Evidence of Cardiac Stem Cells or Proliferative Cardiomyocytes

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Review of “Profiling proliferative cells and their progeny in damaged murine hearts” from PNAS by Stuart P. Atkinson 

While studies have suggested that the differentiation of cardiac stem cells [1] or the division of preexisting cardiomyocytes [2] may contribute to the generation of new cardiomyocytes during the adult mammalian lifetime, doubts still surround the ability of the heart to regenerate post-injury [3]. 

Researchers from the group of Hans Clevers (Hubrecht Institute, Utrecht, The Netherlands) recently identified potential problems associated with related studies and sought to bypass any difficulty by employing a previously described Ki67 knockin reporter mouse models [4] to perform genetic lineage tracing and map proliferative cells in neonatal and adult healthy and damaged heart. 

Reporting in PNAS, Kretzschmar et al. now report a lack of evidence supporting the existence of a quiescent cardiac stem cell population, generation of new cardiomyocytes via transdifferentiation, or the proliferation of significant numbers of cardiomyocytes post-injury [5].

The authors employed single-cell sequencing and genetic lineage tracing employing Ki67 knockin mouse models to generate an exhaustive and unbiased map of proliferating cells and their progeny in normal and post-injury murine hearts as a means to interrogate the existence of cardiac stem cells. This strategy employed the premise that the ability to replace lost cells/tissue through cell division represents the most direct definition of stem cell function. While the study observed cycling cardiomyocytes during the early postnatal stages, only non-cardiomyocyte cell types appeared to transit through the cell cycle in the normal and damaged adult heart. Interestingly, the authors discovered that the proliferating post-damage cardiac fibroblasts that constitute the fibrotic scar to inhibit cardiac rupture exhibited a gene expression profile that closely resembled neonatal cardiac fibroblasts. Overall, the authors discovered no evidence that corroborated the existence of a quiescent cardiac stem cell population, for transdifferentiation of other cell types toward cardiomyocytes, or the proliferation of significant numbers of cardiomyocytes in response to injury.

The authors highlight the lack of specificity of markers previously employed to identify cardiac stem cells and the detection of the proliferation of non-cardiomyocyte lineage cells in the heart as confounding elements in previous studies and hope that their exhaustive and unbiased dataset will now finally resolve any controversy surrounding adult mammalian cardiac regeneration.

For more on the fallout from this new mapping study and all the new findings regarding heart regeneration, stay tuned to the Stem Cells Portal!

References

  1. Beltrami AP, Barlucchi L, Torella D, et al., Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration. Cell 2003;114:763-776.
  2. Senyo SE, Steinhauser ML, Pizzimenti CL, et al., Mammalian heart renewal by pre-existing cardiomyocytes. Nature 2012;493:433.
  3. Eschenhagen T, Bolli R, Braun T, et al., Cardiomyocyte Regeneration. Circulation 2017;136:680-686.
  4. Basak O, van de Born M, Korving J, et al., Mapping early fate determination in Lgr5+ crypt stem cells using a novel K<em>i67‐</em>RFP allele. The EMBO Journal 2014;33:2057-2068.
  5. Kretzschmar K, Post Y, Bannier-Hélaouët M, et al., Profiling proliferative cells and their progeny in damaged murine hearts. Proceedings of the National Academy of Sciences 2018;115:E12245-E12254.