Researchers at the RIKEN Center for Developmental
Biology (CDB) have successfully transplanted retinal
pigment cells derived from stem cells of one monkey
into the eyes of other monkeys without rejection and
without the need for immunosuppressant drugs.
Published in Stem Cell Reports, the study shows that
this procedure is possible as long as a set of cells
called the MHC are genetically matched between the
host monkey and the new retinal cells.
Allogeneic Transplantation of MHC Homozygote iPS-RPE
Cells into Subretinal Space of Control and MHC-Matched
Transplantation of monkey iPS-RPE cells into the
subretinal space in a control monkey (MHC
mismatched) was performed without immunosuppression.
Disc redness in a fundus photograph (upper left) and
slight leakage from the disc in fluorescein
angiography (FA, upper right) were observed at the
8-week (8W) evaluation.
(B) Transplantation of monkey iPS-RPE cells into the
subretinal space in an MHC-matched monkey.
At 8 weeks (8W) after surgery, the results of color
fundus photographs (upper left) and FA (upper right)
revealed no inflammation.
Throughout the 6-month observation period, there
were no rejection signs in the subretinal space or
the retina. Scale bars in color fundus and FA, 1.0
A realistic hope of modern medicine is to replace
damaged tissue with healthy cells grown in the lab.
Currently, adult cells can be reprogrammed into stem
cells, and then re-differentiated and grown into
desired cell types.
The researchers at RIKEN CDB led by Masayo Takahashi
have already begun a clinical transplant trial in
people with age-related macular degeneration.
The team grew retinal pigment cells from induced
pluripotent stem cells (iPSCs) and transplanted them
into the damaged retina of a human participant. In
order to avoid tissue rejection, they used
autologous iPSCs—iPSCs that were created from the
recipient’s own skin cells.
While this method is sound, producing autologous
iPSCs is costly. Additionally, because the cells
must grow at the same rate as they do during normal
development, a person would have to wait more than a
year before a transplant could be performed.
Notes lead author Sunao Sugita, “In order to make
iPSC transplantation a practical reality, the
current goal is to create banks of iPSC-derived
tissues that can be transplanted into anyone as they
are needed. However, immune responses and tissue
rejection are big issues to overcome when
transplanting tissue derived from other
The new study tested a technique called MHC matching
as a way to overcome this issue. Major
histocompatibility complexes (MHCs) are a sets of
cell-surface proteins found in all cells that
function in the immune system. In humans, MHCs are
also called human leukocyte antigens (HLAs). There
are many genetic variations of MHCs, and after
transplantation, if the MHCs of the transplanted
cells are not recognized by the T cells of the host
immune system, there is an immune response and the
tissue is rejected.
To test whether MHC matching is a viable method, the
team used retinal pigment cells that were grown from
monkey iPSCs in the iPS cell bank at the Center for
iPS Cell Research and Application, Kyoto University.
They transplanted the cells into the subretinal
space in monkeys with either genetically matched or
The researchers found that these transplanted cells
survived without rejection for at least 6 months in
MHC-matched monkeys, without using any of the
usually necessary immunosuppressant drugs. In
contrast, rejection was relatively quick in the MHC-mismatched
monkeys. Immunohistochemical examination showed that
infiltration by inflammatory cells was only present
in the transplanted grafts of MHC-mismatched
monkeys. In vitro, the team saw that T cells failed
to respond to the iPSC-derived retinal pigment cells
if they were from an MHC-matched monkey.
In a separate study published in the same issue of
Stem Cell Reports, the researchers saw similar
results when they repeated this last experiment with
human T cells and HLA-matched or unmatched retinal
pigment cells grown from IPSCs.
Now that we have established the lack of immune
response in monkeys and in human cells in vitro,”
explains Sugita, “using the iPS cell bank appears to
be a viable solution, at least in the case of
retinal pigment epithelial cell transplantation.”
"In the next clinical trial,” continues Sugita, “we
plan to use allogeneic iPS-retinal pigment
epithelial cells from HLA homozygote donors. The
clinical data after the transplantation will allow
us to see if the iPS cell bank is truly useful or
not. If so, I think this type of transplantation can
become standard treatment within 5 years.”
For more information
Sunao Sugita, Yuko Iwasaki, Kenichi Makabe, Hiroyuki
Kamao, Michiko Mandai, Takashi Shiina, Kazumasa
Ogasawara, Yasuhiko Hirami, Yasuo Kurimoto & Masayo
Takahashi, "Successful transplantation of retinal
pigment epithelial cells from MHC homozygote iPS
cells in MHC-matched models", Stem Cell Reports, doi:
Sunao Sugita, Yuko Iwasaki, Kenichi Makabe, Takafumi
Kimura, Takaomi Futagami, Shinji Suegami & Masayo
Takahashi, "Lack of T-cell response to iPS
cell-derived retinal pigment epithelial cells from
HLA homozygous donors", Stem Cell Reports, doi: