Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling

Abstract

Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis. We investigated whether intramyocardial gene transfer of naked DNA encoding human Shh (phShh) could promote a favorable effect on recovery from acute and chronic myocardial ischemia in adult animals, not only by promoting neovascularization, but by broader effects, consistent with the role of this morphogen in embryogenesis. After Shh gene transfer, the hedgehog pathway was upregulated in mammalian fibroblasts and cardiomyocytes. This resulted in preservation of left ventricular function in both acute and chronic myocardial ischemia by enhanced neovascularization, and reduced fibrosis and cardiac apoptosis. Shh gene transfer also enhanced the contribution of bone marrow-derived endothelial progenitor cells to myocardial neovascularization. These data suggest that Shh gene therapy may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by triggering expression of multiple trophic factors and engendering tissue repair in the adult heart.

Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells

“…This is accompanied by increased HSC expression of the Hh target gene, Gli2. Shh functions as a morphogen during embryogenesis [7], and promotes remodeling after injury in various adult tissues [13,17,19,21]. Thus, evidence that MFB derived from adult rat primary HSC produce Shh has potentially important implications for remodeling of damaged livers.…”

“…Indeed, the fact that MFB produce a factor that promotes vasculogenesis [15], hematopoiesis [23], and progenitor cell survival [14,41,42] calls into question the wisdom of therapeutic attempts to induce apoptosis in MFB as a strategy for reducing liver fibrosis [48][49][50][51][52]. In other tissues, wound healing is impaired when Shh is inhibited, and accelerates when supplemental Shh is administered [17,21,41,[53][54][55][56].…”

“…For example, Shh promotes vasculogenesis [15,16], cardiac repair [17], neural and skin regeneration [18][19][20][21], bone remodeling [22], and differentiation of hematopoeitic progenitors [23] in adults. Although Hh ligands are not known to regulate liver development during embryogenesis [24], Hh pathway activity has been demonstrated in some cholangiocarcinomas [25] and hepatocellular carcinomas [26][27][28].…”

Accumulation of Hedgehog-Responsive Progenitors Parallels Alcoholic Liver Disease Severity in Mice and Humans

“…45 The likelihood that Hh signaling normally exerts net trophic effects in injured adults, as it does in embryos, is further supported by evidence that injection of Hh ligands improves repair of infarcted myocardium and ischemic neuropathies. 21 However, appropriate constraint of Hh pathway activity is essential for good outcomes because excessive Hh signaling leads to developmental anomalies in embryos 46 and promotes the growth of many types of cancers, including hepatocellular carcinomas and cholangiocarcinomas, in adults. 47 The current results suggest that, by promoting repopulation of injured livers with immature and fibroblastic cells, overactivation of the Hh pathway in adults also has a novel, and more immediate, negative consequence (ie, organ dysfunction).…”

“…14 -16 This insight has potential relevance for liver repair because Hh signaling orchestrates embryogenesis, as well as the remodeling of many adult tissues after injury. [17][18][19][20][21][22][23][24] We reported that bile duct injury is accompanied by strong induction of Hh signaling in portal tract stromal cells and bile ductular cells in both rodents and humans. 16,25 However, it is not clear whether parenchymal liver damage, such as that induced by chronic alcohol consumption, leads to similar activation of Hh signaling.…”