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

Abstract

Growth differentiation factor 11 (GDF11) has been implicated in a variety of aging conditions and the regulation of organ regeneration after injury; however, the role of GDF11 in liver ischemia reperfusion injury (IRI) is unknown. The aim of the current study was to investigate the possible role of GDF11 in liver IRI. We investigated the effects of GDF11 in liver IRI in both young (3 mo) and old (22 mo) mice in vivo, and in primary young and old mouse hepatocytes in vitro. Both serum and hepatic GDF11 protein expression levels increased with age and after IRI. Treatment with recombinant GDF11 significantly increased IRI-induced elevations of serum aminotransferase levels, worsened the histologic status of livers, and impaired liver regeneration. In contrast, inhibition of GDF11 activity with neutralizing Abs significantly decreased liver injury and improved liver regeneration after IRI. In vitro, treatment with recombinant GDF11 significantly delayed cell proliferation in cultured hepatocytes that were subjected to hypoxia/reoxygenation insult. Moreover, suppression of cell-cycle progression may be a key mechanism by which GDF11 inhibited hepatocyte regeneration. Collectively, rather than acting as a rejuvenating agent, GDF11 worsens hepatocellular injury and impairs liver regeneration after IRI.-Liu, A., Dong, W., Peng, J., Dirsch, O., Dahmen, U., Fang, H., Zhang, C., Sun, J. Growth differentiation factor 11 worsens hepatocellular injury and liver regeneration after liver ischemia reperfusion injury.

Growth differentiation factor 11 impairs titanium implant healing in the femur and leads to mandibular bone loss

“…Still, it should also be noted that the present animal experiment provides only preliminary preclinical data, and clinical research unveiling the mysterious relationship between serum GDF11 levels and dental implant healing is needed. Finally, to be consistent and comparable with our previous report as well as the majority of independent laboratories all over the world, [9][10][11]31,32 we adopted systemic administration of rGDF11 or GDF11 antibody. When considering using GDF11 inhibition to enhance implant treatment outcomes in future dental clinics, local delivery of small molecule inhibitors would definitely be a better approach, as it could reduce the dosage and economic burden as well as diminish undesired adverse effects associated with systemic administration of its monoclonal antibody.…”

“…To be comparable with these first findings, follow-up research performed by multiple independent laboratories from all over the world all adopted this strategy when investigating its function in various other organs, such as cardiac muscle, skeletal muscle, 13 brain, 10 kidney, 31 and liver. 32 Therefore, we adopted this dosing regimen in the present study to test whether rGDF11 administration could have similar effects on aging bone. In addition, according to previous reports on the timing of osseointegration in mice, 24 2 weeks after implant insertion represents the early healing stage, when normal young adult mice are able to achieve successful osseointegration.…”

Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells

“…The functions of GDF11 in modulation of age-related dysfunction of heart,4 5 skeletal muscle6–8 and brain9 have been recently investigated. The role of GDF11 in acute liver injury has been investigated recently 10. However, till date, the relevance of GDF11 in the pathophysiology of chronic liver disease and its potential therapeutic application therein remain to be understood.…”

Effects of thiopental in cold ischemia in liver transplantation: An experimental study

“…These solutions were developed based on the principle of organ preservation by balancing the basic metabolic requirements in the process after the organ is removed. However, in spite of this, they can only preserve the viability of the organ taken from the donor for limited periods and the search for new methods to slow organ preservation and metabolism and ensure viability for long periods continues [10][11][12][13][14][15][16][17][18][19].…”