Although the quality of the cells is critical for successful cell therapy, so too is optimization of the environment in which the cells are injected. A new study by the Jun Takahashi group at the Center for iPS Cell Research and Application (CiRA), Kyoto University, reports the benefits of neurexophilin 3 (NXPH3), a secreted peptide that binds to neural surface receptors for the survival and functional development of grafted neurons. Takahashi expects this finding to be an important step in his soon anticipated clinical research using iPSC-derived dopaminergic (DA) neurons for the treatment of Parkinson's disease.

The identification of NXPH3 came after considering a number of candidate proteins that could improve the outcome of transplanted DA neurons. "Inflammation is a major problem in any transplantation, because by definition we are traumatizing the tissue," explains Takahashi. "In addition, the brain of Parkinson's disease patient is under chronic inflammation. Therefore, it is even a bigger problem in Parkinson's disease and causes a large number of cells to die and compromises efficacy." The authors examined Parkinson's disease mouse models under several inflammatory conditions. They prepared DA neurons differentiated from mouse iPS cells and transplanted them into the models, finding that the DA neurons were more likely to survive under acute inflammation than chronic inflammation. The question intriguing the researchers was whether any specific factor was responsible for this difference.

They therefore took a closer look at changes in gene expressions between conditions, finding several candidates that were expressed at higher levels in the acute condition compared with the chronic one. Among these candidates, only NXPH3 improved the survival of DA neurons when injected with the graft. More importantly, NXPH3 showed significantly lower expression in the postmortem brains of human Parkinson's disease patients compared with healthy subjects.

Takahashi is optimistic that the identification of NXPH3 will go a long way in priming the host for cell transplantation. "We have made good progress optimizing the differentiation protocol of iPS cells to DA neurons. The bigger challenge now is preparing the host tissue to accept the graft."

Reference:

Nishimura K, Murayama S, and Takahashi J (2015) Identification of neurexophilin 3 as a novel supportive factor for survival of induced pluripotent stem cell-derived dopaminergic receptors. Stem Cells Translational Medicine.

Online publication: June 3, 2015