Functional heart recovery in an adult mammal, the spiny mouse
Introduction
Ischemic heart disease, particularly myocardial infarction (MI), continues as a major contributor to death, disability, and health resource consumption [1]. Despite advances in management that have markedly improved survival, subsequent cardiac remodeling and heart failure remain critical issues. A central problem in the ischemic-damaged adult mammalian heart is that necrotic myocardial tissue is replaced by non-contractile scar tissue, and spared tissue undergoes considerable remodeling in an attempt to recover ventricular contractile function. Thus, reducing cardiac damage and improving recovery following acute ischemic injury continue to be important targets for management.
In contrast, several non-mammalian vertebrate species such as Urodele amphibians and zebrafish possess a remarkable capacity for cardiac repair and regeneration after apical resection, cryoinjury, or genetic ablation [2] through dedifferentiation and proliferation of cardiomyocytes to replenish damaged myocardium [3,4]. This is also the basis of the regenerative ability of the 1-day-old mouse heart [5]. Regeneration of the mammalian heart has been thought to partially rely on endogenous cardiac stem cells' reactivation, followed by recruitment to the site of injury [6,7]. However, some have suggested that cardiomyocytes can also re-enter the cell cycle [8] through activation of the neuregulin1/ErbB4 signaling pathway [9]. These studies have thus driven a therapeutic approach to cardiac repair in the adult mammal that reawakens proliferative activity in quiescent cardiomyocytes to induce cardiac regeneration.
Strikingly, we and others have observed that the adult spiny mouse (Acomys cahirinus) can regenerate many tissues in response to full-thickness skin, skeletal muscle, ear punches, or kidney damage [[10], [11], [12], [13], [14], [15]]. Consistently across these tissues, lack of fibrosis and collagen deposition in the wound contributes to the regeneration of microvessels, smooth muscle, skeletal muscle, adipose tissue, sebaceous glands, hair follicles, and even ear cartilage without scarring. This significant lack of scarring in Acomys skin prompted us to hypothesize that the same property might be apparent in this adult mammal's heart, which would be very novel. Accordingly, we investigated the functional and cellular responses of the heart following ischemia/infarction-induced myocardial damage. We specifically sought to determine whether Acomys would show a reduced fibrotic reaction to ischemic injury and perhaps even improved functional capacity compared with reference CD1 Mus mice adults.
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Animals and ethics statements
All animal procedures were approved by the Institutional Animal Care and Use Committee at the University of Florida (UF) and complied with the National Institutes of Health and USDA guidelines. Animals were maintained under a 12/12 h light/dark cycle at 25° ± 1 °C, with unrestricted access to food and water. Acomys cahirinus were produced from our colony housed at UF, and the CD1 Mus were purchased from Charles River. Male mice 3–6 months of age were used to avoid differential responses due to
Results
These experiments were based on comparisons between the adult CD1 outbred strain of Mus musculus as a reference and adult Acomys cahirinus (SM). We confirmed by visual inspection of multiple mice and μCT that the anatomy of the coronary arterial system (2-coronary arteries originating from their respective aortic sinuses) was comparable in these two distantly related rodent species.
Acomys and CD1 Mus also exhibited similar heart rates (CD1 433.7 ± 20.6 vs. (SM, Acomys 462.3 ± 12.1 BPM),
Discussion
The most important and novel finding of this study is that adult spiny mice of the genus Acomys possess the capacity to show some restoration of cardiac function and myocardial structure following coronary artery ligation. Thus, Acomys is the first adult mammal with such myocardial recovery, therefore providing a unique model to investigate cardioprotective and regenerative signaling mechanisms in adult mammals.
Acomys has been previously shown to have regenerative capacity in dermal components,
Conclusion
In summary, our analyses on adult Acomys ischemic/infarction damaged hearts show recovery of LV contractile function and the microvasculature, significantly reduced scarring, and increased cell proliferative activity. These findings support the suggestion of a regenerative response, or at least a decreased fibrotic response, in this adult mammal. This would be in accord with other tissues of the adult Acomys body, including skin, ear, and skeletal muscle, suggesting that they appear to be a
Acknowledgments
The authors appreciate the special assistance of Avinash Singh Mandloi, Ruby Goel, Jason O. Brant, Juan Zhang, Lei Wang, and Ashok Kumar. Additionally, we thank Robert A Hromas (past Chair of the Department of Medicine, University of Florida) for funding and Vishu T. Patel and Nishk P. Patel for processing μCT images.
A portion of this work is performed in the McKnight Brain Institute at the National High Magnetic Field Laboratory‘s AMRIS Facility, supported by the National Science Foundation
Sources of funding
This work was funded by NIH HL33610, HL56921 (M.K. Raizada and C.J. Pepine, MPIs), UM1 HL087366 to the Cardiovascular Cell Therapy Research Network (C.J. Pepine), Dean's Office of the College of Medicine, University of Florida (Y.F. Qi and C.J. Pepine), Florida Heart Research Institute/Florida Heart Research Foundation Stop Heart Disease Research Award (Y.F. Qi and C.J. Pepine), and the W.M. Keck Foundation (M. Maden).
Disclosures
No conflicts of interest, financial or otherwise, are declared by the authors.
Data availability statement
Most of the data underlying this article are available in the article and in its online supplementary material. Other data underlying this article will be shared on reasonable request to the corresponding author.
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A remarkable rodent: Regeneration and reproduction in spiny mice (Acomys)
2022, Current Topics in Developmental BiologyCitation Excerpt :The heart provides an intriguing example. Recent work from Malcolm's group suggested that in response to a myocardial infarct, the Acomys heart can recover a good deal of heart function as measured by echocardiography (Qi et al., 2021). More recently, a collaborative effort in Kentucky in parallel with a project at Hubrecht University led by Kerstin Bartscherer's group documented a remarkable resistance to heart injury.
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