Intra-portal TGF-ß delivery by liposomes to stimulate liver regeneration
Description: Acute liver failure due to toxic, viral or surgical resection is a dramatic clinical situation with high mortality. To find new treatments for patients with severe and life-threatening diseases of the liver, a better understanding of the molecular events regulating liver regeneration will be essential. In experimental animal models, it has been established that a complex cellular interplay occurs during liver regeneration. More recently, liver sinusoidal endothelial cells (LSEC) have been shown to be central in the onset of liver regeneration. Furthermore, efficient liver regeneration has been correlated with higher levels of circulating platelets in rodents and humans. However, the mechanisms behind these observations remain largely unknown. One hypothesis is that the release of substances by platelets, directly or indirectly, induces hepatocyte proliferation. However, relevant factors are still not clearly identified. Recent data from in vitro culture studies using mouse LSEC indicated that platelets induce release of IL-6 by LSEC. To identify relevant factors we performed high-performance liquid chromatography, mass spectrometry and biological assays using activated platelet releasates. These set of in vitro experiments allowed us to identify TGF-ß1 as a highly active compound for inducing IL-6 secretion by LSEC. This led us to formulate a new hypothesis proposing that TGF-ß1, released by platelets upon activation in sinusoids, induces secretion of IL-6 by LSEC and thereby triggers liver regeneration. In this project, we will explore in vivo, whether TGF-ß1 derived from platelets is the principal factor for triggering liver regeneration. The innovative aspect of the work will be the technical approaches to analyze the importance of platelet-derived TGF-ß1 in liver regeneration. We plan to use TGF-ß delivery devices (liposomes) in order to investigate whether TGF-ß1 enhances liver regeneration in wild-type mice after 2/3 liver resection, a classical mouse model of liver regeneration. Further, mice deficient for TGF-ß1 in platelets (Plt.TGFß-KO) will be used to evaluate the possibility to rescue liver regeneration by the injection of anionic liposomes delivering associated cationic TGF-ß1 after 2/3 liver resection. To our knowledge, such an approach has never been attempted for liver regenerative medicine where transplantation of stem cells or induced pluripotent cells had been mostly studied.This study has the potential to develop a new approach for supporting liver regeneration by liposomal delivery of growth factors. Liposomes are currently used clinically and could be introduced to improve liver regeneration in patients presenting liver failure.
Amount: CHF 99,980
Funding type: grant
Funder scheme: Spark
Start date: 2020-10-01
End date: 2021-09-30
Investigator: Gonelle-Gispert, Carmen
Institution: University of Fribourg – FR
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 1
Funder award ID: 196301
OpenAlex ID: G7141385220