PMID- 29451335 OWN - NLM STAT- MEDLINE DCOM- 20190820 LR - 20211204 IS - 1549-4918 (Electronic) IS - 1066-5099 (Print) IS - 1066-5099 (Linking) VI - 36 IP - 7 DP - 2018 Jul TI - Mesenchymal Stem Cells Protect Against Hypoxia-Ischemia Brain Damage by Enhancing Autophagy Through Brain Derived Neurotrophic Factor/Mammalin Target of Rapamycin Signaling Pathway. PG - 1109-1121 LID - 10.1002/stem.2808 [doi] AB - Hypoxic-ischemic encephalopathy (HIE) is a serious disease for neonates. However, present therapeutic strategies are not effective enough for treating HIE. Previous study showed that mesenchymal stem cells (MSCs) can exert neuroprotective effects for brain damage, but its mechanism remains elusive. Using in vitro coculture of rat cortical primary neurons and MSCs in HI conditions, we demonstrated that MSCs help increase brain derived neurotrophic factor (BDNF) and autophagy markers (LC3II and Beclin1) in the cultures and decrease cells death (lactate dehydrogenase levels). We demonstrated a similar mechanism using an in vivo rat model of HI in combination with MSCs transplantation. Using a behavioral study, we further showed that MSCs transplantation into the rat brain after HI injury can attenuate behavioral deficits. Finally, we found that the increase in BDNF and autophagy related factors after HI injury combined with MSCs transplantation can be reversed by anti-BDNF treatment and strengthen the point that the protective effects of BDNF work through inhibition of the mammalin target of rapamycin (mTOR) pathway. Collectively, we proposed that coculture/transplantation of MSCs after HI injury leads to increased BDNF expression and a subsequent reduction in mTOR pathway activation that results in increased autophagy and neuroprotection. This finding gives a hint to explore new strategies for treating neonates with HIE. Stem Cells 2018;36:1109-1121. CI - (c) 2018 AlphaMed Press. FAU - Zheng, Zhen AU - Zheng Z AD - Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China. AD - Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, People's Republic of China. AD - Department of Pediatrics, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Zhang, Li AU - Zhang L AD - Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China. AD - Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, People's Republic of China. FAU - Qu, Yi AU - Qu Y AD - Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China. AD - Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, People's Republic of China. FAU - Xiao, Guoguang AU - Xiao G AD - Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China. AD - Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, People's Republic of China. FAU - Li, Shiping AU - Li S AD - Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China. AD - Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, People's Republic of China. FAU - Bao, Shan AU - Bao S AD - Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China. AD - Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, People's Republic of China. FAU - Lu, Q Richard AU - Lu QR AD - Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China. AD - Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, People's Republic of China. FAU - Mu, Dezhi AU - Mu D AUID- ORCID: 0000-0001-5072-4072 AD - Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China. AD - Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, People's Republic of China. LA - eng GR - R01 NS072427/NS/NINDS NIH HHS/United States GR - R01 NS075243/NS/NINDS NIH HHS/United States GR - R37 NS096359/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180305 PL - England TA - Stem Cells JT - Stem cells (Dayton, Ohio) JID - 9304532 RN - 0 (Brain-Derived Neurotrophic Factor) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) MH - Animals MH - Autophagy MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Disease Models, Animal MH - Humans MH - Hypoxia, Brain/*metabolism MH - Hypoxia-Ischemia, Brain/*metabolism MH - Mesenchymal Stem Cells/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*genetics PMC - PMC6657778 MID - NIHMS1041707 OTO - NOTNLM OT - Autophagy OT - Brain damage OT - Brain derived neurotrophic factor OT - Hypoxia-ischemia OT - Mammalian target of rapamycin OT - Mesenchymal stem cells COIS- Disclosure of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. EDAT- 2018/02/17 06:00 MHDA- 2019/08/21 06:00 PMCR- 2019/07/25 CRDT- 2018/02/17 06:00 PHST- 2017/10/12 00:00 [received] PHST- 2018/02/06 00:00 [revised] PHST- 2018/02/10 00:00 [accepted] PHST- 2018/02/17 06:00 [pubmed] PHST- 2019/08/21 06:00 [medline] PHST- 2018/02/17 06:00 [entrez] PHST- 2019/07/25 00:00 [pmc-release] AID - 10.1002/stem.2808 [doi] PST - ppublish SO - Stem Cells. 2018 Jul;36(7):1109-1121. doi: 10.1002/stem.2808. Epub 2018 Mar 5.