Next stage of iPS cells


Induced pluripotent stem (aka iPS) cells are pluripotent stem cell generated directly from adult cells.  The iPS cell technology was discovered by a team led by Shinya Yamanaka, the chief of the Center for iPS Cell Research and Application (aka the CiRA Laboratory) at Kyoto University, Japan.  The finding was that introducing four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells.  He was awarded the Nobel Prize in Physiology or Medicine 2012 jointly to Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."



Image source: CiRA homepage



Research teams at the CiRA Laboratory, the government-affiliated RIKEN Institute, and other research institutes are setting up efforts to conduct clinical studies for transplanting tissues made from heterologous cells into patients.  Although the "heterologous transplantation" poses a risk of immune rejection, it could be more advantageous in time and cost than the "autologous transplantation".  The Japanese-original iPS cells are going to be advanced to a new stage where they could be clinically used.


Risk of Immune Rejection


Masayo Takahashi, the project leader of the RIKEN Institute, who conducted a transplant surgery in 2014, the first in the world, for a patient suffering from "age-related macular degeneration," which is a serious eye disease, is producing cell sheets of a retinal tissue from iPS cells delivered from the CiRA Laboratory and transplanting them to patients.


The iPS cells are autologous pluripotent cells that can be converted into cells of a desired tissue.  Although autologous cells are free of immune rejection, why are the research teams using heterologous cells that are subject to immune rejection?


The first reason is to reduce time necessary to make desired cell seats.  Two years ago, Takahashi's team spent 10 months to convert skin cells of the patient into iPS cells and make a cell sheet of a retinal pigment epithelium.  If preserved iPS cells are used, the cell sheet could be made earlier than the autologous iPS cells by about four months.


The second reason is to reduce cost necessary to do that.  If iPS cells are clinically made, it would cost more than \50,000,000 (US$420,000).  Since iPS cells can be propagated indefinitely, if heterologous iPS cells are used, it would not be necessary to make them corresponding to individual patients.


The iPS cells are likely concerned with cancerization and teratoma.  In the surgery conducted by the Takahashi's team, iPS cells were made without oncogenes.  In addition, all the genes of the iPS cells were carefully checked for safety.  "We spent more than \50,000,0000 to evaluate the entire genome (gene information)," Shinya Ymanaka, who was in charge of verification for the genes of the iPS cells, said in a lecture held in 2014.


If iPS cells were made from autologous cells of individual patients, whenever the iPS cells are used, they need to be checked for safety.  However, if heterologous iPS cells are used, since they would have been checked for their safety, high quality iPS cells could be used.  As a result, the transplanted tissue would cost less than \10,000,0000.


However, if heterologous cells are transplanted into a patient, there would be a risk of immune rejection.  If the type of the protein "HLA" of the patient matches that of iPS cells, the immune rejection could be suppressed to some extent.  From a mouse study, the Takahashi's teach has confirmed that the heterologous cells are safe.  "If we properly select iPS cells, the immune rejection could be remarkably suppressed," said Takahashi. 



CiRA supporting research teams with preserved iPS cells


The CiRA Laboratory at Kyoto University is providing "heterologous" iPS cells.  The laboratory is preserving iPS cells that have been checked for safety so that the preserved iPS cells can be readily used for treatments.  The laboratory has been proposing the "iPS cell preservation" plan for five years since the foundation of the laboratory.


According to the plan, the CiRA Laboratory is going to collect several ten types of iPS cells whose HLA types are different and freeze-preserve them.  Immune cells identify whether transplanted cells are heterologous (foreign) cells.  However, since the HLA type of some iPS cells match those of many people, if iPS cells having an HLA type that matches that of a patient are selected, the risk of immune rejection would be decreased.


The CiRA Laboratory is starting delivering preserved iPS cells to research teams at Keio University, RIKEN Institute, and so forth.  A research team at Osaka University has received iPS cells in the autumn of 2015 and converted them into myocytes of a heart.  The research team is going to treat a patient having a serious heart disease with myocytes made from the iPS cells.  "Our team is coming close to a stage of clinical applications," said Yoshiki Sawa, the leader of the research team at Osaka University.  He also said that his team is checking the iPS cells for safety and efficiency.


A research team at Keio University is planning to treat patients having spinal cord injuries with preserved iPS cells.  Hideyuki Okano, the leader of the research team at Keio University said that if the spinal cord is injured, the patient needs to undergo a transplant surgery for the injured spinal cord in several weeks after the injury.  He also said that his team is going to convert the provided iPS cells into graft cells and preserve them.  "Preserved iPS cells delivered from the CiRA Laboratory are essential to transplant high quality graft cells into the spinal cord of a patient in four weeks after the spinal cord injury," said Hideyuki Okano.



iPS; regenerative medicine;