Effects of vitamin C on cytotherapy-mediated muscle regeneration.
Skeletal muscles are the largest organs in the human body, and several therapeutic trials have been conducted that included stem cell transplantation to regenerate damaged or wasted muscles. It is well known that it is essential to make a favorable microenvironment (stem cell niche) to induce the proper differentiation of the transplanted stem cells. Some drugs, such as losartan (angiotensin II type I blocker), enhance the therapeutic effects of transplanted stem cells by inhibiting fibrosis. In this study, we hypothesized that another substance, vitamin C (ascorbic acid), might improve the niche for stem cell transplantation based on its potent antioxidant effects. In both gross and microscopic observations, vitamin C-depleted mice exhibited more incomplete regeneration of damaged muscles than those treated with vitamin C. Carbonylated protein groups, which are the end products of oxidative stress, were detected in all experimental groups; however, the vitamin C-depleted groups exhibited a more potent positive reaction than that of the vitamin C-supplied groups. The difference is clearer in the presence of transplanted stem cells. Moreover, the serum total vitamin C level and the ascorbic acid (AA) to dehydroascorbic acid (DHA) ratio also were decreased in the presence of transplanted adipose-derived stem cells (ASCs). Taken together, these data can be considered as proof of vitamin C utilization by cells in vivo. The vitamin C-supplied groups displayed more severe fibrosis than that of the vitamin C-depleted groups. Since vitamin C is a major cofactor for the collagen synthesis, its deficiency resulted in reduced fibrosis. In conclusion, we demonstrated that vitamin C not only has a positive effect on adjusting the stem cell niche to boost muscle regeneration but also has an adverse aspect due to its profibrotic effect.
Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea.
Ah-Young
AY
Kim
Eun-Mi
EM
Lee
Eun-Joo
EJ
Lee
Chang-Woo
CW
Min
Kyung-Ku
KK
Kang
Jin-Kyu
JK
Park
Il-Hwa
IH
Hong
Akihito
A
Ishigami
Jacques P
JP
Tremblay
Kyu-Shik
KS
Jeong
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000097:blood / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D003683:Dehydroascorbic Acid / Q000097:blood; D005260:Female; D005355:Fibrosis / Q000209:etiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D017570:MyoD Protein / Q000378:metabolism; D051763:PAX7 Transcription Factor / Q000378:metabolism; D012038:Regeneration; D000076223:Regulatory-Associated Protein of mTOR; D055153:Stem Cell Niche; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D002135:Calcium-Binding Proteins; D024042:Collagen Type I; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D017570:MyoD Protein; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D000076223:Regulatory-Associated Protein of mTOR; C513324:Rgn protein, mouse; C540162:Rptor protein, mouse; D053773:Transforming Growth Factor beta1; D058570:TOR Serine-Threonine Kinases; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid