Meeting/Workshop

Symposium "hiPSC and organoids in disease modeling and neurogenetics" organized by IGBMC

October 10, 2023

Illkirch-Graffenstaden (France)

INTRODUCTION

 

Human induced pluripotent stem cells (hiPSCs) have become the model of choice for studying human pathologies in vitro. These cells can be differentiated in 2D or 3D models to mimic complex systems (organs, cellular interactions) in normal or pathological conditions. The symposium will bring together four guests who will present their use of hiPSCs to decipher the biological mechanisms underlying human neurological disorders. In particular, our guests will present cerebral, retinal and intestinal/pancreatic organoids as well as neuro-muscular junctions derived from hiPSCs.

 

This 3rd mini-symposium is organised by the Translational Medicine and Neurogenetics Department of the IGBMC based in Illkirch-Graffenstaden (Strasbourg, France), in collaboration with Inserm, the University of Strasbourg and the CNRS. This symposium is led by Manon BOIVIN (PhD), Marianne LEMEE (PhD candidate) and Pierre TILLIOLE (PhD candidate).

PROGRAM

 

Program

 

09:00-09:45 am

Ira M. Espuny Camacho (online) - University of Liege, Belgium

"Decoding intrinsic features of human brain maturation and disease using brain organoïds"

The maturation of the human brain shows species-specific differences of neoteny when compared to lower mammals. This process encompass a time window that expands from late embryonic stages to early adolescence. Major features of brain maturation are the acquisition of phenotypic complex traits such as axonal and dendritic trees and the presence of dendritic spines which correlate with higher functionality and connectivity of the neurons. Interestingly, human transcriptomic data has shown a narrow time window from the birth of the individual to the first two years of life where major transcriptomic changes occur. Among those changes, there is an striking accumulation of alternative splicing events such as the splicing of the MAPT gene (TAU), whose role is essential in several neurodegenerative conditions such as Alzheimer’s disease. Here, we address human-specific species features of brain maturation using a multicellular human in vitro brain organoid model composed of neurons and glia cell types. Long-term human brain organoids are analysed functionally for the acquisition of mature neuronal phenotypes to understand the time line of maturation compared to the in vivo situation. Further, we show that human brain organoids can recapitulate hallmarks of AD such as high levels of amyloid beta species,Tau phosphorylation and neuronal function alterations in vitro.

 

09:50-10:35 am

Olivier Goureau - Institut de la Vision, Paris, France

"Generation of retinal organoïds: new insights into human development and disease"

Inherited and acquired degenerative diseases of the outer retina, characterized by the death of light-sensitive photoreceptors, are a significant cause of incurable vision loss worldwide. Rescuing the degenerated retina is a major challenge for which human induced pluripotent stem cells (iPSCs) offer a wide range of applications from cell transplantation to disease modelling. We elaborated innovative protocols for the production of self-forming retinal organoids from human iPSCs. We will present recent strategies based on the use of retinal organoids for cell therapy and optogenetics. We will discuss how the use of patient-specific iPSCs can be used to explore the molecular and cellular mechanisms of specific genetic mutations leading to retinal degenerative diseases and to validate gene therapy approaches.

 

11:00-11:45 am

Rudolf Rüdiger - Mannheim University of Applied Sciences, Germany

"Towards a tripartite hiPSC-derived neuromuscular junction model: progress and challenges"

Core neuromuscular junctions (NMJs) are tripartite synapses in the peripheral nervous system formed by motor neurones, skeletal muscle fibres, and terminal Schwann cells. To build neuromuscular disease models for personalised medicine, derivation of these cell types from human induced pluripotent stem cells (hiPSC) would be useful. However, while protocols for hiPSC-derived motor neurones have been working robustly, reliable differentiation of Schwann cells and muscle cells was difficult. Therefore, in previously established neuromuscular cell models these cell types were either not present at all or they were replaced by rodent or primary cells. We have established protocols (i) to differentiate Schwann cells from hiPSC in a robust manner by tuning of BMP signalling activity during the differentiation, (ii) for further maturation of Schwann cells in medium which is specifically composed to be compatible with neuromuscular tricultures, and (iii) to set up tricultures of hiPSC-derived Schwann cells and hiPSC-derived motor neurones in combination with murine C2C12 muscle cells. In 2D tricultures, we demonstrate colocalization of all cell types at sites positive for post-synaptic muscle acetylcholine receptor, and effects of cocultured cell types on myotube growth and receptor plaques. Currently, we are also working on improved protocols for the generation of hiPSC-derived muscle cells and plan to integrate them into fully human neuromuscular triculture models in 2D and 3D.

 

11:50 am-12:35 pm

Valérie Schreiber - IGBMC, Strasbourg, France

"Deciphering the gene regulatory networks controlling human pancreatic and intestinal endocrine differentiation using stem cell derived organoids"

Future strategies for cell replacement therapies and regenerative medicine strongly depend on our knowledge of the detailed mechanisms that control the differentiation of multipotent stem cells into highly specialized cells. Along these lines of research, our goal is to dissect the molecular mechanisms controlling endocrine cell diversity and maintenance of the endocrine phenotype in the pancreas and intestine. This research is part of an effort to understand the mechanisms underlying the pathophysiology of pancreatic (diabetes) and intestinal hormone deficiencies (malabsorption). While significant progress has been obtained in these topics in rodents, our knowledge in human is scarce due to the lack of an appropriate model system. This limitation has been overcome with the emergence of pluripotent stem cell-based human organoids, a model system that we now use together with gene editing and multi-omics approaches to study the transcriptional regulatory networks that control the differentiation, subtype specification and functional maturation of endocrine cells in the human pancreas and intestine.

 

 

DATES AND VENUE

Date: Oct. 10th, 2023 (from 09.00 to 12.35)

Venue: IGBMC, 1 rue Laurent Fries, Illkirch-Graffenstaden (Auditorium)

Registration: here