Mass production of vascularised liver organoids from human pluripotent stem cells.
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Mass production of vascularised liver organoids from human pluripotent stem cells.
Wed, 17/06/2020 - 14:30 to 15:30
Speaker:
Gareth Sullivan
Affiliation:
University of Oslo.
Synopsis:
A lack of physiological parity between 2D and in vivo has paved the way towards more organotypic models. Organoid models have been developed for many cell types, including hepatic organoids. However current approaches suffer a number of drawbacks, including a heavy reliance on extracellular matrices (ECM) to support cystic organoid growth, costly growth factors and in a physiological context, a lack of cellular complexity and vasculature. Recent advances have added vasculature albeit at a later point or via transplantation in vivo1,2. Another consideration is the ability to scale the production of organoids in a cost effective manner. Current hepatic organoid models are generally simplistic, composed of hepatocytes or cholangiocytes, rendering them less physiologically relevant as compared to native tissue. To address these shortcomings, we have developed an ECM independent approach combined with small molecules to produce massive quantities of 3D “mini-liver” organoids. The organoids have enhanced function, and can be maintained long term. Importantly, the mini livers contain the major cell types of the native liver sinusoid including the parenchymal, non-parenchymal cell types and vascular structures. This could serve as an inexpensive approach to produce massive quantities of liver-like tissue with enhanced function and maturity, a pre-requisite for a myriad of applications from cellular therapy, tissue engineering, drug toxicity assessment, disease modeling, and basic developmental research.
References:
1. Cakir B, Xiang Y, Tanaka Y, et al. Engineering of human brain organoids with a functional vascular-like system. Nat Methods. 2019;16(11):1169‐1175. doi:10.1038/s41592-019-0586-5
2. Mansour AA, Gonçalves JT, Bloyd CW, et al. An in vivo model of functional and vascularized human brain organoids. Nat Biotechnol. 2018;36(5):432‐441. doi:10.1038/nbt.4127
Biography:
Dr. Gareth Sullivan - is a group leader within the Pediatric Research Institute, Oslo University Hospital and a PI at the Hybrid Technology Hub - Centre of Excellence, University of Oslo. He holds a PhD in molecular cell biology from the University of Dundee, Scotland and performed his post-doctoral research at the Centre of Regenerative Medicine, University of Edinburgh with Sir Prof. Ian Wilmut. In addition he has over 8 years industrial experience, as a CSO, working in both the toxicology and next generation sequencing fields. At the end of 2011 he established his own research group at the University of Oslo and Oslo University Hospital. Where his research focus turned to what dictates cellular fate decision, along with the utilization of induced pluripotent stem cells (iPSCs) to study disease in the dish. The overall focus of the lab now is the development of tissue models using human pluripotent stem cells that reflect the in vivo organ, thus allowing the dissection of disease, provide tools to investigate toxicology, reduce drug failure rates and importantly enable regenerative medicine. The Sullivan group was first to demonstrate the generation of functional hepatocyte like cells from human iPSCs derived from different ethnic backgrounds (Hepatology, 2010). This work has led to the establishment of the first small molecule driven hepatocyte differentiation procedure (Stem Cell Reports, 2015) and has now been translated to large-scale 3D liver organoid production (manuscript submitted), ultimately to provide a more physiological model.