Medicine by Design and the Ontario Institute for Regenerative Medicine co-funded New Ideas Grants for the following projects in 2015:
Heart tissue repair via immune cell growth factors
Project Leader: Slava Epelman
University Health Network
Project Description: Very young hearts are able to fully regenerate after injury, while adult hearts cannot. In the young heart, this regeneration is dependent on primitive immune cells called macrophages that enter the heart during embryonic development. Importantly, these primitive macrophages are also found in the heart of adults (mice and humans). Following a heart attack in adult mice, primitive macrophage numbers are significantly reduced within the damaged zone of the heart. This project is focused on harnessing the regenerative properties of primitive cardiac macrophages. In the proposed studies, we will isolate primitive cardiac macrophages following a heart attack in mice and then determine which growth factors produced by these primitive macrophages promote important repair functions. If successful, future studies will focus on how we can deliver the identified growth factors to the injured heart in order to promote cardiac tissue repair.
Projected Outcomes: We will define the growth factors produced by primitive macrophages that drive heart tissue regeneration following heart attack.
Intestinal stem cells and gut microbiota in early postnatal development and necrotizing enterocolitis
Project Leader: Tae-Hee Kim
SickKids Research Institute
Project Description: The intestine is a vital organ that absorbs nutrients and forms a physical barrier against the outside environment. The lining of the intestine is continuously self-renewed throughout life by stem cells located in the crypt, a pocket-like intestinal gland. At birth, newborns face dramatic environmental changes, among them the introduction of gut microbiota. Although proper intestinal development requires gut microbiota, its influence on intestinal stem cell maturation is unclear. Compromised intestinal development in newborns exposed at birth to the external environment leads to serious diseases, such as necrotizing enterocolitis (NEC), one of the most deadly gastrointestinal diseases in human infants. Currently, how NEC initiates is unknown. This project will investigate whether developmental defects in intestinal stem cells and their altered interaction with gut microbiota underlie the immature intestine and are responsible for NEC initiation. Using mice as a model system, the team will investigate signaling and transcriptional mechanisms of intestinal stem cell differentiation, as well as the role of gut microbiota during development.
Projected Outcomes: This work will define the significance of intestinal stem cells and their differentiated cell populations in development and necrotizing enterocolitis (NEC), as well as identify new biomarkers for infant gut diseases. It will facilitate the development of intestinal stem cell based therapy for NEC.
Activating enhancers to improve reprogramming efficiency
Project Leader: Jennifer Mitchell
Department of Cell & Systems Biology, University of Toronto
Project Description: Regenerative medicine approaches ideally rely on the efficient generation of patient-specific induced pluripotent (iPS) cells. However, this is impeded by the cost, time taken and the low efficiency of the reprogramming process. The expression of the Sox2 gene is a late but required event in the reprogramming process and represents a barrier to reprogramming. This project will establish a more effective reprogramming technique that can be applied to human patient-derived cells using CRISPR activation of reprogramming genes and their associated regulatory regions. The team will focus on activation of the endogenous Sox2 gene which currently presents a significant barrier to establishing fully reprogrammed cells. In addition, activation of Sox2 in the context of stem cell differentiation can improve the efficiency of neural differentiation. This work will later be expanded to include the regulatory regions for other genes that present barriers to reprogramming and may provide a faster and more efficient way to generate patient specific cells for personalized regenerative medicine.
Projected Outcomes: Increased efficiency in generating patient specific iPS cells for regenerative medicine through epigenetic modulation.
Injectable, tissue-engineered scaffold for delivery of cardiac patches
Project Leader: Milica Radisic
Institute of Biomaterials & Biomedical Engineering and Department of Chemical Engineering & Applied Chemistry, University of Toronto
Project Description: In the developed world, cardiovascular disease is responsible for the loss of more human lives than all cancers combined. Tissue engineering aims to regenerate or replace damaged tissues in an effort to improve the state of organ health. However, high-fidelity and structurally compatible tissue patches cannot be easily delivered to the body in a minimally invasive way. For delivery of a cardiac patch, open heart surgery is currently required. This project proposes a system by which thick cardiac tissues may be delivered to the heart via injection. The team will design a biocompatible, shape-retaining, injectable, and self-assembling tissue scaffold that is based on two technologies previously developed in the Radisic lab. This scaffold will then be injected in vivo in a layer-by-layer approach, achieving the building up of tissue with organized structure in three dimensions.
Projected Outcomes: Creation of a tissue scaffold compatible with minimally invasive delivery to the body to assemble cardiac patches in vivo. This technology would result in a facile, rapid, and cost-effective approach to production of functional and scalable heart tissues, and in a revolution in the clinical applications of tissue engineering.
Dissolving scar tissue in spinal cord injuries improve candidacy and effects of stem cell transplants
Project Leader: Charles Tator
University Health Network
Project Description: Stem cells from the brain or spinal cord are currently used in clinical trials in patients with chronic spinal cord injury (SCI). However, only a small number of patients have been treated, and the outcome is uncertain. The presence of scar tissue at the site of injury may prevent effective regrowth of nerve fibers, thus dissolving the scar may improve the effects of subsequent stem cell transplants. An enzyme named chondroitinase has been available for the past 15 years and has shown very favorable experimental results in experimental SCI. However, there has been no practical and safe way of giving this enzyme to patients with SCI. This team has invented a new form of this enzyme which lasts more than one week and can be administered safely and effectively, without the need for direct injection or indwelling catheters and pumps. This project will test this enzyme in a rat model of cervical SCI. The technology for making this enzyme in clinical amounts and to clinical standards is already accomplished, and so there is definite potential for use of this agent in humans and commercialization.
Projected Outcomes: Development of a practical strategy for delivering an enzyme to dissolve the scar tissue that forms in the spinal cord after injury, which is essential for making stem cell transplantation effective in humans with spinal cord injury.
Biomimetic surfaces for directed differentiation of lung stem cells
Project Leader: Tom Waddell
Toronto General Research Institute, University Health Network
Division of Thoracic Surgery & Institute of Biomaterials & Bioengineering, University of Toronto
Description: Current systems for the study of lung epithelium are inadequate. Traditionally, alveolar epithelial cells (AECs) are grown on flat surfaces, which do not replicate the environment within the alveoli of the lung. Cells grown on decellularized scaffolds partially mimic AEC maturation, however, the complexity of decellularized scaffolds makes it difficult to identify and control the specific cues necessary to direct AEC development. This project has three goals. First, it will develop a simple, physiologically relevant cell culture system that better models the architecture of the alveolus. Second, it will study the capacity of lung stem cells to grow in these cavities and differentiate along an AEC lineage. Finally, it will produce a platform that also incorporates dynamic stretch, another physiologically relevant mechanical cue. Using this biomimetic construct, the team will assess maturation of lung stem cells in the presence and absence of stretch signals.
Projected Outcomes: The proposed dynamic culture system will advance in vitro modelling of distal lung providing more suitable platforms for:
- disease modelling and evaluation of novel therapies;
- patient-specific drug screening;
- understanding cellular biology of airway epithelial cells;
- modeling pulmonary cell-based therapeutic applications; and
- generation of more suitable cell sources for cell therapy.