Regeneration of skeletal and cardiac muscle in mammals: do nonprimate models resemble human pathology?

Abstract

Most of the available information regarding the regenerative potential and compensatory remodeling of mammalian tissues has been obtained from nonprimate animals, mainly rodent experimental models. The increasing use of transgenic mice for studies of the mechanisms controlling organogenesis and regeneration also requires a clear understanding of their applicability as experimental models for studies of similar processes in humans and other mammals. Application of modern cell biology methods to studies of regenerative processes has provided new insights into similarity and differences in cellular responses to injury in the tissues of different mammalian species. During more than 200-million years of progressive divergent evolution of mammals, cellular mechanisms of tissue regeneration and compensatory remodeling evolved together with increasingly adaptive functional specialization and structural complexity of mammalian tissues and organs. Rodents represent a phylogenetically ancient order of mammals that has conservatively retained a number of morphofunctional characteristics of early representatives of this class, which include enhanced regenerative capacity of tissues. A comparative analysis of regenerative processes in skeletal and cardiac muscle, as well as in several other mammalian tissues, shows that time courses and intensities of regeneration in response to the same type of injury vary even within taxonomically related species (e.g., rat, mouse, and hamster). The warm bloodedness of mammals facilitated the development of more complex mechanisms of metabolic, immune, and neurohumoral regulation, which resulted in a stronger dependence of regenerative processes on vascularization and innervation. For this reason, interspecies modifications of regenerative responses are limited by the capacity of the animal to resorb rapidly the foci of necrosis and to revascularize and reinnervate the volume of the regenerating tissue. These differences, among other factors, result in significantly lower rates of reparative regeneration in mammals possessing larger body sizes than rodents. A review of these data strongly indicates that the phylogenetic age and biological differences between different species should be taken into account before extrapolation of regenerative properties of nonprimate tissues on the regenerative responses in the primates.

Model Systems for Cardiovascular Regenerative Biology

“…For instance, regeneration of skeletal muscle following injury can act as a model for myocyte regeneration in more easily accessible tissue (Borisov 1999). In addition, although mammalian heart regeneration is limited, studying model organs such as the skin (Palatinus et al 2010) or liver (Badylak et al 2012) that do continue to regenerate into adulthood in humans, can provide us with clues on the underlying principles of regeneration of relevance to the heart.…”

Cell Transplantation and “Stem Cell Therapy” in the Treatment of Myopathies: Many Promises in Mice, Few Realities in Humans

“…Given also that the regenerative capacity of mice is different from that of humans [105], it would be appropriate to explore this phenomenon also in animal models more similar to humans.…”

Rx for tissue restoration: Regenerative biology and medicine

“…For example, minced muscle regenerates well in rats, less well in larger animals such as guinea pig, rabbit, cat, and dog, and not at all in humans (Borisov, 1999). Larger muscle masses may fail to regenerate because of difficulties with revascularization and innervation, and slow resorption of degenerating myofibers.…”

“…Muscle regeneration is poorer in older rats than younger ones. I" minced muscle is reciprocally transplanted between old and young rats, the quality of regeneration changes t match that of the host, implying that it is the local and/or systemic environment that determines regenerative quality, not changes in the ability of satellite cells to respond (Borisov, 1999).…”