Targeted myocardial delivery of GDF11 gene rejuvenates the aged mouse heart and enhances myocardial regeneration after ischemia–reperfusion injury

Abstract

Ischemic cardiac injury is the main contributor to heart failure, and the regenerative capacity of intrinsic stem cells plays an important role in tissue repair after injury. However, stem cells in aged individuals have reduced regenerative potential and aged tissues lack the capacity to renew. Growth differentiation factor 11 (GDF11), from the activin-transforming growth factor β superfamily, has been shown to promote stem cell activity and rejuvenation. We carried out non-invasive targeted delivery of the GDF11 gene to the heart using ultrasound-targeted microbubble destruction (UTMD) and cationic microbubble (CMB) to investigate the ability of GDF11 to rejuvenate the aged heart and improve tissue regeneration after injury. Young (3 months) and old (21 months) mice were used to evaluate the expression of GDF11 mRNA in the myocardium at baseline and after ischemia/reperfusion (I/R) and myocardial infarction. GDF11 expression decreased with age and following myocardial injury. UTMD-mediated delivery of the GDF11 plasmid to the aged heart after I/R injury effectively and selectively increased GDF11 expression in the heart, and improved cardiac function and reduced infarct size. Over-expression of GDF11 decreased senescence markers, p16 and p53, as well as the number of p16 cells in old mouse hearts. Furthermore, increased proliferation of cardiac stem cell antigen 1 (Sca-1) cells and increased homing of endothelial progenitor cells and angiogenesis in old ischemic hearts occurred after GDF11 over-expression. Repetitive targeted delivery of the GDF11 gene via UTMD can rejuvenate the aged mouse heart and protect it from I/R injury.

Growth differentiation factor 11 worsens hepatocellular injury and liver regeneration after liver ischemia reperfusion injury

“…Zhang et al (14) demonstrated that GDF11 improved renal repair, recovery of renal function, and survival of old elderly mice after IRI. Du et al (15) reported that the targeted delivery of the GDF11 gene to the heart via ultrasound-targeted microbubble destruction could rejuvenate the aged mouse heart and protect against subsequent IR insult. Differences may be a result of the tissue specificity of GDF11 expression, and the function of GDF11 may be cell type specific.…”

“…As the controversial role of GDF11 in aging pathologies and GDF11 was able to reduce IRI in kidneys (14) and heart (15) of aged mice, we therefore investigated the role of GDF11 in liver IRI in aged mice. Consistent with that observed young mice, recombinant GDF11 administration led to severe liver damage in aged mice in response to IRI, as demonstrated by higher serum aminotransferase levels and more severe histopathologic abnormalities (Supplemental Fig.…”

“…GDF11 was proposed to decline with age and to restore young tissue function phenotypes in the heart (11), brain (12), and skeletal muscle (13). GDF11 function has also been implicated in IRI of the kidneys (14) and heart (15) in elderly mice. Clinical studies suggest that GDF11 may play a protective role against aging-associated muscular frailty in humans (16) and may be associated with the cellular senescence observed in patients with chronic obstructive pulmonary disease (17).…”

GDF11 Attenuates Development of Type 2 Diabetes via Improvement of Islet β-Cell Function and Survival

“…Very importantly, Poggioli et al (14) confirmed that administration of recombinant GDF11 (rGDF11) reverses cardiac hypertrophy in both young and old mice. Furthermore, GDF11 promotes the recovery of renal and cardiac function in old mice (15,16).…”

“…Very importantly, Poggioli et al (14) confirmed that administration of recombinant GDF11 (rGDF11) reverses cardiac hypertrophy in both young and old mice. Furthermore, GDF11 promotes the recovery of renal and cardiac function in old mice (15,16).Information regarding the role of GDF11 in pancreatic islets is scarce, however. Early studies showed that mice lacking GDF11 exhibited markedly reduced b-cell numbers and arrested b-cell development (6).…”