Xenografted human amniotic membrane-derived mesenchymal stem cells are immunologically tolerated and transdifferentiated into cardiomyocytes.
BACKGROUND
Amniotic membrane is known to have the ability to transdifferentiate into multiple organs and is expected to stimulate a reduced immunologic reaction.


OBJECTIVE
Determine whether human amniotic membrane-derived mesenchymal cells (hAMCs) can be an ideal allograftable stem cell source for cardiac regenerative medicine.


RESULTS
We established hAMCs. After cardiomyogenic induction in vitro, hAMCs beat spontaneously, and the calculated cardiomyogenic transdifferentiation efficiency was 33%. Transplantation of hAMCs 2 weeks after myocardial infarction improved impaired left ventricular fractional shortening measured by echocardiogram (34+/-2% [n=8] to 39+/-2% [n=11]; P<0.05) and decreased myocardial fibrosis area (18+/-1% [n=9] to 13+/-1% [n=10]; P<0.05), significantly. Furthermore hAMCs transplanted into the infarcted myocardium of Wistar rats were transdifferentiated into cardiomyocytes in situ and survived for more than 4 weeks after the transplantation without using any immunosuppressant. Immunologic tolerance was caused by the hAMC-derived HLA-G expression, lack of MHC expression of hAMCs, and activation of FOXP3-positive regulatory T cells. Administration of IL-10 or progesterone, which is known to play an important role in feto-maternal tolerance during pregnancy, markedly increased HLA-G expression in hAMCs in vitro and, surprisingly, also increased cardiomyogenic transdifferentiation efficiency in vitro and in vivo.


CONCLUSIONS
Because hAMCs have a high ability to transdifferentiate into cardiomyocytes and to acquire immunologic tolerance in vivo, they can be a promising cellular source for allograftable stem cells for cardiac regenerative medicine.
Department of Obstetrics, Keio University School of Medicine, Tokyo, Japan.
Hiroko
H
Tsuji
Shunichiro
S
Miyoshi
Yukinori
Y
Ikegami
Naoko
N
Hida
Hironori
H
Asada
Ikuko
I
Togashi
Junshi
J
Suzuki
Masaki
M
Satake
Hikaru
H
Nakamizo
Mamoru
M
Tanaka
Taisuke
T
Mori
Kaoru
K
Segawa
Nobuhiro
N
Nishiyama
Junko
J
Inoue
Hatsune
H
Makino
Kenji
K
Miyado
Satoshi
S
Ogawa
Yasunori
Y
Yoshimura
Akihiro
A
Umezawa
D000650:Amnion / Q000166:cytology* / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation; D036861:Delivery, Obstetric; D004452:Echocardiography; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006321:Heart / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D023001:Transplantation Tolerance; D014183:Transplantation, Heterologous / Q000502:physiology*; D016277:Ventricular Function, Left / Q000502:physiology