Through the program of ThéCell Research Projets the network supports collaboration between members of the network and allows these research partnerships to develop new original research projects. To be admissible a project must comprise at least 3 members of ThéCell from at least two institutions.
The program exists since 2009. The funding period of these projects was from April 1st, 2018 to March 31st, 2019.
|Title and abstract||AXE|
|To study neurofibromatosis throught patient-derived tissue-engineered skins and facilitate the discovery of new therapeutic targets||I.|
|François Gros-Louis (Centre LOEX du CRCHU de Québec – Université Laval) François Berthod (Centre LOEX du CRCHU de Québec – Université Laval), Marie-Noelle Hébert-Blouin (Département de neurologie de l’Université McGill)
Neurofibromatosis type 1 (NF1) is a hereditary neurocutaneous disease that is highly stigmatizing and for which there is no cure. It is caused by mutations decreasing the activity of the neurofibromin protein. The occurence of benign skin tumors, called neurofibromas, is one of the hallmarks of the disease. These are masses of cells enriched in Schwann cells. Our hypothesis is that solid skin neurofibromas are more prone to emerge in a tissue-engineered skin model when it is entirely derived from the patient's cells. Our main goals are to develop an innovative tissue-derived skin model derived from patients and to use it to better understand this disease, as well as stimulate preclinical and transltational research. To build the model, we will use fibroblasts and keratinocytes isolated from cutaneous biopsies. In addition, Schwann cells derived from pluripotent induced cells genetically modified strains to induce a loss of function of neurofibromine to 2 alleles and then to model human NF in a model of skin reconstructed in the laboratory. Any innovative treatment that will stop the growth of neurofibromas could have a positive effect on the overall survival of patients.
|Engineering a vascularized immunoisolation device to treat diabetes: optimizing the blood-device interface||II.|
|Corinne Hoesli (Université McGill /Dépt. de génie chimique), Steven Paraskevas (Institut de recherche du centre universitaire de santé McGill), André Bégin-Drolet (Université Laval, Département de génie mécanique)
Type 1 diabetes is an autoimmune disease where the immune system attacks the insulin-producing beta cells of the pancreas. People suffering from this disease control their
blood glucose levels using insulin injections or infusion. Even with scientific progress in this field, this approach leads to risks of hypoglycemia (glucose too low) and cardiovascular
Instead of replacing insulin, islet transplantation is a long-term therapeutic approach based on replacing the beta cells. Our team performed the first islet transplants in Québec. Over 70% of the patients receiving islet grafts will live without needing insulin injections for at least two years. Access to this therapy is limited by donated organ supply. Moreover, the immune suppression medication required to avoid graft rejection is associated with unwanted side effects.
The goal of this research project is to design a transplantation device to avoid islet rejection and enable the use of stem cells instead of islets from organ donors. This device would avoid the need for immune suppression, improve treatment outcome and increase the number of patients that have access to this cellular therapy.
|Optimizing cell therapy by combining cell encapsulation and pharmacological conditioning||II.|
|Sophie Lerouge (Ecole de technologie supérieure (ÉTS)), Shant Der Sarkissian (Université de Montréal/ Chirurgie), Nicolas Noiseux(Université de Montréal/ Chirurgie), Corinne Hoesli Université McGill), Denis-Claude Roy (Université de Montréal/ CETC)
The clinical benefit of current cell therapies is limited by various factors, such as the low retention of injected cells, their poor survival in the tissues and the variability of their phenotype.
The objective of this project is to demonstrate the potential of the combination of technologies developed by several Quebec teams, namely encapsulation and pharmacological preconditioning, to counter these limits and improve the effectiveness of these treatments. We have recently demonstrated in vitro the major benefits of pharmacological preconditioning on stem cells, alone and macro-encapsulated in a chitosan hydrogel, in terms of survival, growth and pro-angiogenic paracrine activity. This funding will be used both to establish in vivo evidence of the efficacy and safety of these technologies and to demonstrate that they can be applied to different cell types, also when the cells are encapsulated in microspheres.
The first targeted clinical application is the treatment of ischemic diseases such as myocardial infarction, for which our team is already involved in clinical trials. In the longer term, other clinical applications are targeted, including islet encapsulation to treat type 1 diabetes, encapsulation of T lymphocytes for cancer immunotherapy, and stem cell encapsulation to combat osteoarthritis, in collaboration with a French research team.
|Determination of a predictive biomarker for extracellular matrix deposition to form a three-dimensional tissue.||III.|
|Véronique Moulin (CR CHU de Québec - Université Laval/ Chirurgie/LOEX), Sylvain Guérin (CR CHU de Québec - Université Laval/ Ophtalmologie/LOEX), Jean-François Beaulieu (Université de Sherbrooke)
The LOEX laboratory reconstructs skins using tissue-engineering methods to treat patients with extensive burns. Production is performed in vitro and the reconstructed skin is ready to be grafted after approximately 52 days. This delay is essentially due to the production of the dermis that, in turn, rely on the property of the fibroblasts to produce and deposit the extracellular matrix around the cells. As this method is very dependent on the donor's cells, for each new donor, several questions arise: will the deposition of matrix be sufficient to be manipulated and after how long? Will the dermis strongly contract during production? The goal of this project is to determine a biological parameter to answer these questions as soon as possible after receiving the biopsy. To that purpose, we will compare the ability of fibroblasts to produce a dermis with the presence of specific extracellular matrix proteins as well as with the presence of the marker responsible for the contraction of the tissue. These biomarkers will improve the production process of the reconstructed skins, and in the future, will reduce the delay between reception of the biopsy and grafting of the reconstructed skin to the patient.
|T lymphocytes cross-reactivity between the gut microbiota and lung cancer||IV.|
|Bertrand Routy (CHUM/CRCHUM), André Marette (Université de Laval), Réjean Lapointe (CHUM/CRCHUM)
The immune system of patients living with cancer is altered and immunotherapy represents a major breakthrough for various cancers. Immune checkpoint inhibitors (ICI) are a new class of medication that re-awakens the immune system toward cancer cells. Unfortunately, despite unprecedented results, 70% of patients still progress. Recently, we showed that the gut microbiota was in part responsible for ICI efficacy. Indeed, modification of the microbiota by antibiotics before starting ICI decrease their efficacy in lung cancer. We also identified that patients enriched with Akkermansia muciniphila bacteria have a stronger clinical response.
The objective of this project is to evaluate the microbiota composition in patients with limited stage lung cancer in collaboration with Dr. Marette (Université Laval) and to study the link between the gut microbiota, immune system and tumor. We will study the cross-reactivity of T lymphocytes receptor between Akkermansia muciniphila and the tumor. Furthermore, we aim to better understand T lymphocytes trafficking from the gut toward the tumor. Indeed, increasing T lymphocytes migration within the tumor bed would increase ICI therapeutic index. Ultimately, this study will better characterize the role of the microbiota on immune response to provide novel therapeutic approach to increase ICI activity.