PMID- 23081858
OWN - NLM
STAT- MEDLINE
DCOM- 20130624
LR  - 20211203
IS  - 1549-4918 (Electronic)
IS  - 1066-5099 (Linking)
VI  - 31
IP  - 1
DP  - 2013 Jan
TI  - mTORC1 and mTORC2 play different roles in the functional survival of transplanted 
      adipose-derived stromal cells in hind limb ischemic mice via regulating 
      inflammation in vivo.
PG  - 203-14
LID - 10.1002/stem.1265 [doi]
AB  - Poor cell survival severely limits the beneficial effects of stem cell therapy 
      for peripheral arterial disease (PAD). This study was designed to investigate the 
      role of mammalian target of rapamycin (mTOR) in the survival and therapeutic 
      function of transplanted murine adipose-derived stromal cells (mADSCs) in a 
      murine PAD model. mADSCs (1.0 x 10(7)) were isolated from dual-reporter firefly 
      luciferase and enhanced green fluorescent protein-positive transgenic mice, 
      intramuscularly implanted into the hind limb of C57BL/6 mice after femoral artery 
      ligation/excision, and monitored using noninvasive bioluminescence imaging (BLI). 
      Although engrafted mADSCs produced antiapoptotic/proangiogenic effects in vivo by 
      modulating the inflammatory and angiogenic cytokine response involving the mTOR 
      pathway, longitudinal BLI revealed progressive death of post-transplant mADSCs 
      within ~4 weeks in the ischemic hind limb. Selectively targeting mTOR complex-1 
      (mTORC1) using low-dose rapamycin treatment with mADSCs attenuated 
      proinflammatory cytokines (interleukin [IL]-1beta and tumor necrosis factor-alpha 
      [TNF-alpha]) expression and neutrophil/macrophage infiltration, which overtly 
      promoted mADSCs viability and antiapoptotic/proangiogenic efficacy in vivo. 
      However, targeting dual mTORC1/mTORC2 using PP242 or high-dose rapamycin caused 
      IL-1beta/TNF-alpha upregulation and anti-inflammatory IL-10, IL-6, and vascular 
      endothelial growth factor/vascular endothelial growth factor receptor 2 
      downregulation, undermining the survival and antiapoptotic/proangiogenic action 
      of mADSCs in vivo. Furthermore, low-dose rapamycin abrogated TNF-alpha secretion by 
      mADSCs and rescued the cells from hypoxia/reoxygenation-induced death in vitro, 
      while PP242 or high-dose rapamycin exerted proinflammatory effects and promoted 
      cell death. In conclusion, mTORC1 and mTORC2 may differentially regulate 
      inflammation and affect transplanted mADSCs' functional survival in ischemic hind 
      limb. These findings uncover that mTOR may evolve into a promising candidate for 
      mechanism-driven approaches to facilitate the translation of cell-based PAD 
      therapy.
CI  - Copyright (c) 2012 AlphaMed Press.
FAU - Fan, Weiwei
AU  - Fan W
AD  - Department of Cardiology & Molecular Imaging Program, Fourth Military Medical 
      University, Xi'an, Shaanxi, China.
FAU - Cheng, Kang
AU  - Cheng K
FAU - Qin, Xing
AU  - Qin X
FAU - Narsinh, Kazim H
AU  - Narsinh KH
FAU - Wang, Shenxu
AU  - Wang S
FAU - Hu, Sijun
AU  - Hu S
FAU - Wang, Yabin
AU  - Wang Y
FAU - Chen, Yundai
AU  - Chen Y
FAU - Wu, Joseph C
AU  - Wu JC
FAU - Xiong, Lize
AU  - Xiong L
FAU - Cao, Feng
AU  - Cao F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Stem Cells
JT  - Stem cells (Dayton, Ohio)
JID - 9304532
RN  - 0 (Interleukin-1beta)
RN  - 0 (Interleukin-6)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 0 (enhanced green fluorescent protein)
RN  - 130068-27-8 (Interleukin-10)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 1.13.12.7 (Luciferases, Firefly)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adipocytes/metabolism
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Proliferation
MH  - Cell Survival
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - Femoral Artery/surgery
MH  - Green Fluorescent Proteins/genetics
MH  - Hindlimb/blood supply/metabolism
MH  - Inflammation/metabolism
MH  - Interleukin-10/biosynthesis
MH  - Interleukin-1beta/biosynthesis
MH  - Interleukin-6/biosynthesis
MH  - Ischemia/*metabolism/surgery
MH  - Luciferases, Firefly/genetics
MH  - Luminescent Measurements
MH  - Macrophages/immunology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Multiprotein Complexes/*metabolism
MH  - Neovascularization, Pathologic
MH  - Neutrophils/immunology
MH  - Peripheral Arterial Disease/*metabolism/therapy
MH  - Proteins/*metabolism
MH  - Sirolimus/pharmacology
MH  - Stromal Cells/*metabolism/transplantation
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tumor Necrosis Factor-alpha/biosynthesis/drug effects
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor Receptor-2/biosynthesis
MH  - Vascular Endothelial Growth Factors/biosynthesis
EDAT- 2012/10/20 06:00
MHDA- 2013/06/26 06:00
CRDT- 2012/10/20 06:00
PHST- 2012/05/01 00:00 [received]
PHST- 2012/09/19 00:00 [revised]
PHST- 2012/09/23 00:00 [accepted]
PHST- 2012/10/20 06:00 [entrez]
PHST- 2012/10/20 06:00 [pubmed]
PHST- 2013/06/26 06:00 [medline]
AID - 10.1002/stem.1265 [doi]
PST - ppublish
SO  - Stem Cells. 2013 Jan;31(1):203-14. doi: 10.1002/stem.1265.