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, 2017 to March 31st, 2018.
|Title and abstract||AXE|
|Preclinical study of the bone healing potential of a new biological bone filler substitute||I.|
| François A. Auger, Julie Fradette, Nathalie Faucheux, Michel Fortin
After dental extraction, a loss of alveolar bone volume can occur in the oral cavity. In order to maximize the success of dental implant placement, the surgeon will often fill the defect using a cell-free biomaterial. However, these can cause inflammatory reactions, leading to an additional loss of bone volume and hampering the success of the implant. Our laboratory has developed a human osseous tissue lacking exogenous biomaterial by utilizing a self-assembly technique that takes advantage of the ability of adipose-derived stem/stromal cells (hASCs) to differentiate into bone cells while simultaneously secreting a mineralized extracellular matrix. This preclinical study will evaluate bone healing in rodent alveolar defects filled with our novel tissue-engineered substitutes with or without bone morphogenetic protein-9 peptides. Collaboration with a maxillofacial surgeon on this project allows us to focus on future clinical translation. Indeed, we believe these human cell-based bone substitutes have the potential to improve several parameters of oral bone healing in patients, reducing postoperative complications.
|Enhancing Muscle Stem Cell Engraftment using the Feldan Shuttle Technology||I.|
|Florian Bentzinger, Jacques P. Tremblay, Alain Garnier, Frédéric Balg
Muscular dystrophies cause progressive failure of the contractile function of skeletal muscle that is due to instable muscle fibers and scarring. Theoretically, the ability of muscle stem cells (MuSCs) to fuse to each other and form new multinucleated muscle fibers, or to add their nuclei to existing fibers, makes these cells ideal candidates for stem cell therapy of these conditions. Unfortunately, limited amounts of MuSC can be isolated from donors and it has been attempted to expand the cells in-vitro to obtain sufficient cell numbers. However, once cultured, MuSC downregulate expression of the stem cell maintenance factor Pax7 and convert into myoblasts that have reduced engraftment and tissue dispersal potential. Here, we outline a project that employs the Feldan Shuttle Technology to deliver the transcription factor Pax7 to myoblasts. We postulate that reintroduction of Pax7 to these cells will restore their stem cell character and enhance their engraftment potential in dystrophic muscle. We will test this hypothesis by assessing the efficiency of transplantation of Feldan-Pax7 treated myoblasts in dystrophic mice and primates. Ultimately, our work will establish a novel strategy to boost the stem cell character of myoblast so that they can be exploited for stem cell therapy.
|Precision stem cell pharmaco-optimization for improved clinical responsiveness in cell therapy trials for heart failure||II.|
| Nicolas Noiseux, Denis-Claude Roy, Shant Der Sarkissian, Samer Mansour, Sophie Lerouge, Julie Fradette, Philippe Comtois, Jonathan Ledoux, Jean-François Tanguay
Although stem cell transplantation for treating damage caused by infarction (heart attack) demonstrates a certain level of effectiveness, therapeutic benefit remains marginal due to several factors including the phenotype of cells used and their poor survival when delivered in a diseased heart. Our team has completed two clinical studies (IMPACT-CABG and COMPARE-AMI) where patients having suffered from a heart attack were treated with their own stem cells. Using banked samples of these cells, we propose to study the correlation between the phenotypic and gene expression profile of these cells with the patients’ clinical response (function and volume of the cardiac cavities). This will allow to identify the populations of cells and the pattern of gene expression responsible for therapeutic effectiveness. Next, we will use this information to select pharmacological compounds targeting these precise expression patterns in order to treat the stem cells before their transfer in patients. We will measure the response of different cell types to these molecules, measure the effect of pre-treated stem cells in animal models of infarction and evaluate different methods of cell transfer including their encapsulation in biomaterials. Our data will be used to improve cell therapy and prepare the next generation of clinical studies.
|Liver organoids as a model system for studying metastatic melanoma therapeutic resistance||III.|
| Solange Landreville, Massimiliano Paganelli, François A. Auger
Uveal melanoma is the most common eye tumor in adults, and the second most frequent type of melanoma after the skin. Liver metastasis is a dreaded complication of these cancers. The patients face limited treatment options, and too often they fail. Previous works suggest that the microenvironment has a significant impact on the inefficacy of treatments. Hepatic stromal cells surrounding metastases, such as hepatic stellate cells, are promoting metastatic progression in various cancers. Our highly innovative project proposes to use human liver organoids derived from stem cells as models to better understand the balance between the melanoma cell dormancy and the invasion of the surrounding tissue, as well as the concomitant therapeutic resistance. Any innovative treatment that will stop the growth of the melanoma cells in the liver might turn the fatal metastatic stage into a chronic disease, thus impacting the overall survival of patients.
|Development of Cell Therapy for Diabetes Using Mesenchymal Stem Cells Expressing Islet Neogenesis-Associated Protein (INGAP).||III.|
| Lawrence Rosenberg, Julie Fradette, Nicoletta Eliopoulos
Diabetes is a life-threatening disease characterized by the complete (Type 1; T1DM) or partial (Type 2, T2DM) destruction of insulin-producing β-cells in the pancreas. We propose to design a novel stem-cell based therapy to stimulate regeneration of β-cells from the patient’s own cells. Published evidence supports that regeneration of β-cells occurs at low levels even in people with long-standing T1DM. We hypothesize that this process can be stimulated by Mesenchymal Stem Cells (MSCs) gene-modified to produce a regenerating protein, INGAP (Islet Neogenesis Associated Protein). INGAP and its bio-active fragment, INGAP-peptide, have been shown to reverse diabetes in animals by inducing β-cell regeneration. INGAP-peptide is in phase II clinical trials, and has shown positive effects on glucose homeostasis in T1DM and T2DM patients. MSCs, stem cells present in adults, secrete growth factors with beneficial effects like immunomodulation. We and others have shown that MSCs can be used for targeted delivery of therapeutic gene products. Our experimental aims are to: 1) generate human MSCs producing INGAP (INGAP-MSCs); 2) evaluate the potency of INGAP-MSCs to influence cell-fate and cell-multiplication in culture; 3) examine the in vivo anti-diabetic potential of INGAP-MSCs using diabetic mice. Our novel approach is expected to significantly advance diabetes research.
|Alloreactive T cell depletion as a novel treatment of acute cellular rejection in renal transplant patients.||IV.|
| Denis-Claude Roy, Lynne Senécal, Jean-Pierre Routy, Collette Suzon, Heloise Cardinal, Amhad Imran
Acute cellular rejection is a major issue after kidney transplantation. The patient’s immune cells target the donor kidney and threaten the function and the survival of the transplanted organ. Potent immunosuppressive drugs are given to treat rejection, but these can have severe side effects and cause diabetes, gastrointestinal problems, cataracts, repeated or severe infections and cancer. A novel photodynamic cell therapy is available that can remove the damaging activated immune cells while sparing T cells that can control the immune system. We want to apply this therapy for the treatment of acute cellular rejection. The objective of our study is to test a new treatment plan for safety and feasibility in a pilot clinical trial of a few patients, setting the stage for a larger clinical trial. We believe that this treatment will control the immune cells causing the rejection and also induce tolerance to the donor kidney. This treatment could change the approach to rejection following solid organ transplantation, improving the survival and quality of life of patients receiving organ transplants.