Growth factor enhancement of mammalian regeneration

Abstract

The remarkable potential of lower vertebrates to rebuild heart and skeletal muscle contrasts with relatively poor regenerative capacity in mammals, which may not retain a sufficiently robust progenitor cell population into adulthood. Regeneration of the mammalian myocardium is perhaps the most recalcitrant, having apparently lost the ability to activate localized dedifferentiation of postmitotic cells that accompanies heart regeneration in lower vertebrates. Myogenic progenitors were enhanced in regenerating transgenic mouse muscle expressing a local insulin-like growth factor-1 (mIGF-1) isoform, which maintains tissue integrity during exercise and aging, counters muscle decline in degenerative disease and cachexia, and enhances healing following injury. After cardiotoxin-induced damage, regenerating mIGF-1 transgenic muscles rapidly down-regulated markers of inflammation, suggesting that resolution of the inflammatory response is an important component of efficient regeneration. In hearts expressing the same mIGF-1 transgene under the control of a cardiac-specific promoter, heightened expression of physiologic but not pathologic markers of cardiac growth and hypertrophy in postnatal mIGF-1 hearts was accompanied by sustained increases in protein translational components and decreases in specific markers of inflammation. The regenerative capacity of mIGF-1 transgene expression was directly compared in heart and skeletal muscle by myocardial infarction of wild-type and transgenic mice, producing localized damage, cell death, and massive inflammation in both genotypes. In contrast to wild-type controls, transgenic mIGF-1 expression resulted in enhanced repair of the injured heart with reduced scar formation and displayed increased proliferation in the area of damage after 1 month. Down-regulation of specific inflammatory cytokines suggests that IGF-1 improves cardiac regeneration in part by modulation of the inflammatory response. Since supplementary expression of mIGF-1 does not alter normal heart development or long-term postnatal cardiac growth and function, the enhancement of cardiac regeneration by localized expression of this growth factor suggests novel and clinically feasible therapeutic strategies to decrease inflammation and increase cell proliferation.