Multipotent mesenchymal stem cell grafting to treat cutaneous radiation syndrome: development of a new minipig model.
OBJECTIVE
Cutaneous radiation syndrome (CRS) is the delayed consequence of localized skin exposure to high doses of ionizing radiation. Recent grafting of three ionizing radiation-burned patients has suggested the benefit of local bone marrow mesenchymal stem cell (MSC) injection in favor of wound healing and pain control. Here, we have developed a new minipig model of severe CRS to study underlying mechanisms of this cell therapy approach.


METHODS
Göttingen minipigs were locally irradiated using a (60)Co gamma source as follows: ungrafted 50 and 60 Gy (n = 4) and grafted 50 and 60 Gy (n = 3). Bone marrow MSCs were cultured in minimum essential medium with 10% fetal calf serum and basic fibroblast growth factor (2 ng.mL(-1)). Autologous MSCs were intradermally injected twice or three times from days 27 to 96 (range, 99-128.5 × 10(6) MSCs per injection).


RESULTS
All animals exhibited a clinical evolution similar to humans after a latency phase of several weeks, including early erythema, hair loss, and dry/moist desquamation followed by necrosis during 81 to 222 days post-ionizing radiation. Skin damage in higher exposed animals appeared slightly earlier. Immunohistology revealed severe skin damage in all animals and rhabdomyolysis in the muscle tissue below the entry area, with the latter being more severe in controls. In grafted animals, MSCs led to local accumulation of lymphocytes at the dermis/subcutis border and improved vascularization.


CONCLUSIONS
This study establishes a new minipig model that is close to human and allows development of stem cell therapy strategies that can be applied in treatment of human radiation burns.
Agay
Diane
D
IRBA-antenne La Tronche-CRSSA, La Tronche, France.
Scherthan
Harry
H
Forcheron
Fabien
F
Grenier
Nancy
N
Hérodin
Francis
F
Meineke
Viktor
V
Drouet
Michel
M
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D062109:Dermatologic Surgical Procedures; D004195:Disease Models, Animal; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D007271:Injections, Intradermal; D015603:Keratinocytes / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D011833:Radiation Injuries, Experimental / Q000601:surgery*; D012867:Skin / Q000473:pathology / Q000528:radiation effects; D013552:Swine; D013556:Swine, Miniature; D018800:Thy-1 Antigens / Q000378:metabolism; D013997:Time Factors; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D018960:Hyaluronan Receptors; D019394:Ki-67 Antigen; D018800:Thy-1 Antigens; D019010:Vascular Cell Adhesion Molecule-1; D016222:Fibroblast Growth Factor 2