Malin Parmar
Lund University
Sweden
DEVELOPING BETTER MODELS FOR LONG-TERM SURVIVAL OF HUMAN EMBRYONIC STEM CELLS IN IMMUNE-COMPETENT HOSTS
Swedish Research Council
163,221
01/01/2016
2
The neurons in our brain have no capacity to regenerate and thus diseases or traumatic injuries resulting in neuronal death is hard to treat. One promising alternative is to replace the lost neurons by transplanting new, functional cells. To achieve this type of brain repair, there is a great, unmet need to develop human neurons from stem cells or other renewable sources. When a new potential cell source has been developed, it as to be extensively evaluated in pre-clinical animal models before use in patients. These transplantation experiments are absolutely essential in order to bring these stem cell-based therapies to use in patients; yet xenografting of human cells into the rodent model is problematic and poses a number of practical and ethical issues. Current methods for immunosuppression and prevention of graft rejection that are widely used today consist of daily intraperitoneal (i.p) injections of ciclosporin, grafting into new born animals or using immune compromised hosts (athymic nude rats). These models area associated with several complications for the research animals: daily injections require extensive handling and thus increased stress to the animals, there is an increased risk for infection, and with daily injections one risk perforation of intestines with subsequent peritonitis as a result. When use athymic nude rats there is no need for daily injections, however the animals are not suitable for repeated behavioral assessment and also very sensitive to infections risking premature termination of experiments. In this proposal we will develop a new method for xenografting that does not require daily injections or immune compromised hosts, yet allows for the type of long term assessments needed to validate stem cell derived neurons in a rat model of PD. The method includes inoculation of stem cell derived neurons to new born rats and is based on the idea that when the adaptive immune system is exposed to the foreign cells during its early learning phase it will later fail to recognize the cells used for inoculation as foreign and thus not reject the grafted cells when transplanted as adults. Ones implemented it will reduce the number of animals needed per experiment, replace the need for athymic nude rats and greatly refine the conditions for the animal as it require less handling, no daily injections and no increased risk of infections