Cell Therapy for the Intestinal Tract (Wake Forest Institute for Regenerative Medicine)

Cell Therapy for the Intestinal Tract

Principal Investigator: Graça Almeida-Porada

Research Team: Joana Boura, Christopher Porada

At WFIRM, SENS Research Foundation is funding Dr. Graça Almeida-Porada’s group in a project to restore intestinal structure and function. Dr. Almeida-Porada’s central goal in this project is the development of a regenerative medicine approach to treating inflamma- tory bowel disease (IBD), an autoimmune disorder that devastates the cells lining the intestine. IBD incidence does rise with age, but SRF’s main reason for support- ing this research is because therapies that repopulate the cells of the gut will be critical to the development of a new generation of cancer therapies that are likely to depopulate the stem cell reserves of several tissues and replace the missing cells with fresh, cancer-protected stem cells. Furthermore, regenerative therapies for the gut would be of enormous value to people receiving many existing cancer therapies that ravage intestinal tissue, such as radiation therapy during treatment for pelvic or abdominal cancer.
 
The WFIRM researchers are developing a combination cell therapy based on the transplantation of modified human mesenchymal stem cells (hMSC), which have potent anti-inflammatory/immunomodulatory effects to protect them from attack by the body’s immune system. The researchers used a model of IBD in which naïve CD4+ T-cells from healthy, normal mice are repeatedly infused into mice with mutations that prevent them from produc- ing their own immune cells. In such mice, inflammation develops throughout the length of the large intestine and produces symptoms reminiscent of human IBD.
 
The WFIRM researchers then took the IBD-model mice and divided them into four groups: one receiving unmodified human MSC, another receiving hMSC modified to increase their anti-inflammatory potential, and a third group receiving hMSC modified to have both anti-inflammatory potential and to migrate specifically to the deep pockets (“crypts”) of the gut lining where stem cells normally reside. The final group was kept as controls. This research is ongoing, but results so far indicate that mice that received hMSC modified to increase their anti-inflammatory potential suffered significantly less weight drop than all of the other groups — including the mice whose transferred cells were further modified to enhance homing to the crypt.
 
The WFIRM team determined that the inclusion of the crypt-homing transgene was blocking the anti-inflammatory transgene in the same construct. The cells in this case homed into their target, but were unable to exert a robust therapeutic effect. The team will now develop and test a new construct including both transgenes and thereby evaluate the true potential of combining these two features in the therapeutic cells. Further analysis is being performed to fully characterize and quantify the benefit of the different cell therapies on intestinal inflammation at the immunological and microscopic tissue level.