Rapid communicationA systematic analysis of neonatal mouse heart regeneration after apical resection
Introduction
The discovery by Porrello et al. in 2011 that neonatal mice have the potential to regenerate resected myocardium generated much excitement in cardiovascular biology [1]. A recent study by Andersen et al. questioned the utility of the apical resection model [2]. Andersen et al. found that extensive scarring occurred in apically resected hearts at 21 days post-surgery and found limited evidence for neomyogenesis [2]. Understandably, the conflicting results produced by this study has generated some confusion and controversy as several laboratories have produced data that the neonatal mouse heart does have regenerative capabilities and is able to undergo neomyogenesis after sustaining myocardial injury [3]. Much speculation has occurred as to why the Porrello and Anderson studies appear to conflict, and it is possible that technical considerations as well as determining how regeneration is defined are important [3], [4], [5].
We systematically examined how technical considerations influence this important experimental model. These considerations included the size of apical resection, which was posited to be one cause for the conflicting findings, as well as the mechanical fixation (surgical retraction) of the ventricle during surgery [3]. We aimed to systematically and quantitatively clarify the extent of regeneration, neomyogenesis, and scarring that occur in this model. We show that new myocardial formation clearly occurs after apical resection, but that this regeneration is often accompanied by some scarring at 21 days post-resection (dpr). The extent of scarring is related to resection size. We also show that there is an increase in cardiomyocyte cell cycle activity, but fibrosis and an increase in cardiomyocyte cell cycle activity occur when sham operations include surgical retraction; the surgical retraction effect in control hearts can mask the induction of cardiomyocyte cell cycle activity in resected hearts. These data clarify the neonatal mouse apical resection model.
Section snippets
Surgical procedures
Neonatal mice were anesthetized for 4 min on ice. We performed thoracotomy followed by resection of either 10 or 20% of the ventricle. Our typical sham operation did not involve mechanically fixing the apex of the left ventricle. For non-retracted sham operations, we performed thoracotomy without resection. For surgical retraction experiments, we gently fixed the left ventricle with a microneedle holder after open thoracotomy.
Statistical analysis
Data are presented as mean ± SEM. A one-way ANOVA followed by a pairwise
Scarring often accompanies new heart muscle formation after apical resection and is related to resection size
To study the impact of resection size, we measured the relative size of the resected myocardium (Supplemental Fig. 1A). As intended, large resections were approximately twice as large as moderate resections (Supplemental Fig. 1B). After quantifying the weights of hearts at 3 h post-surgery, we found that moderate and large resections removed about 10% and 20% of the ventricular myocardium respectively (Fig. 1A). Thus, we were able to quantitatively distinguish that resection size, and the sizes
Funding sources
This work was supported by an HHMI Gilliam Fellowship (D.M.B.), an NIH National Research Service Award (C.C.O.), and grants from the NIH (AG040019 and HL117986 to R.T.L.).
Disclosure statement
None.
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Do neonatal mouse hearts regenerate following heart apex resection?
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