PMID- 30352880
OWN - NLM
STAT- MEDLINE
DCOM- 20190325
LR  - 20200309
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 68
IP  - 1
DP  - 2019 Jan
TI  - Dysregulation of Nrf2/Keap1 Redox Pathway in Diabetes Affects Multipotency of 
      Stromal Cells.
PG  - 141-155
LID - 10.2337/db18-0232 [doi]
AB  - The molecular and cellular level reaches of the metabolic dysregulations that 
      characterize diabetes are yet to be fully discovered. As mechanisms underlying 
      management of reactive oxygen species (ROS) gain interest as crucial factors in 
      cell integrity, questions arise about the role of redox cues in the regulation 
      and maintenance of bone marrow-derived multipotent stromal cells (BMSCs) that 
      contribute to wound healing, particularly in diabetes. Through comparison of 
      BMSCs from wild-type and diabetic mice, with a known redox and metabolic 
      disorder, we found that the cytoprotective nuclear factor erythroid-related 
      factor 2 (Nrf2)/kelch-like erythroid cell-derived protein 1 (Keap1) pathway is 
      dysregulated and functionally insufficient in diabetic BMSCs (dBMSCs). Nrf2 is 
      basally active, but in chronic ROS, we found irregular inhibition of Nrf2 by 
      Keap1, altered metabolism, and limited BMSC multipotency. Forced upregulation of 
      Nrf2-directed transcription, through knockdown of Keap1, restores redox 
      homeostasis. Normalized Nrf2/Keap1 signaling restores multipotent cell properties 
      in dBMSCs through Sox2 expression. These restored BMSCs can resume their role in 
      regenerative tissue repair and promote healing of diabetic wounds. Knowledge of 
      diabetes and hyperglycemia-induced deficits in BMSC regulation, and strategies to 
      reverse them, offers translational promise. Our study establishes Nrf2/Keap1 as a 
      cytoprotective pathway, as well as a metabolic rheostat, that affects cell 
      maintenance and differentiation switches in BMSCs.
CI  - (c) 2018 by the American Diabetes Association.
FAU - Rabbani, Piul S
AU  - Rabbani PS
AUID- ORCID: 0000-0001-8302-8225
AD  - Hansjorg Wyss Department of Plastic Surgery, New York University School of 
      Medicine, New York, NY piul.rabbani@nyumc.org daniel.ceradini@nyumc.org.
FAU - Soares, Marc A
AU  - Soares MA
AD  - Hansjorg Wyss Department of Plastic Surgery, New York University School of 
      Medicine, New York, NY.
FAU - Hameedi, Sophia G
AU  - Hameedi SG
AD  - Hansjorg Wyss Department of Plastic Surgery, New York University School of 
      Medicine, New York, NY.
FAU - Kadle, Rohini L
AU  - Kadle RL
AD  - Hansjorg Wyss Department of Plastic Surgery, New York University School of 
      Medicine, New York, NY.
FAU - Mubasher, Adnan
AU  - Mubasher A
AD  - Hansjorg Wyss Department of Plastic Surgery, New York University School of 
      Medicine, New York, NY.
FAU - Kowzun, Maria
AU  - Kowzun M
AD  - Hansjorg Wyss Department of Plastic Surgery, New York University School of 
      Medicine, New York, NY.
FAU - Ceradini, Daniel J
AU  - Ceradini DJ
AD  - Hansjorg Wyss Department of Plastic Surgery, New York University School of 
      Medicine, New York, NY piul.rabbani@nyumc.org daniel.ceradini@nyumc.org.
LA  - eng
GR  - P30 CA016087/CA/NCI NIH HHS/United States
GR  - S10 OD010584/OD/NIH HHS/United States
GR  - S10 OD018338/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20181023
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (SOXB1 Transcription Factors)
RN  - 0 (Sox2 protein, mouse)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cell Differentiation/physiology
MH  - Diabetes Mellitus, Experimental/*metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Immunohistochemistry
MH  - Immunophenotyping
MH  - Kelch-Like ECH-Associated Protein 1/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-E2-Related Factor 2/*metabolism
MH  - Oxidation-Reduction
MH  - Oxidative Stress/physiology
MH  - Reactive Oxygen Species/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - SOXB1 Transcription Factors/metabolism
MH  - Signal Transduction/physiology
MH  - Stromal Cells/*cytology/*metabolism
PMC - PMC6302538
EDAT- 2018/10/26 06:00
MHDA- 2019/03/26 06:00
PMCR- 2020/01/01
CRDT- 2018/10/25 06:00
PHST- 2018/02/28 00:00 [received]
PHST- 2018/10/09 00:00 [accepted]
PHST- 2018/10/26 06:00 [pubmed]
PHST- 2019/03/26 06:00 [medline]
PHST- 2018/10/25 06:00 [entrez]
PHST- 2020/01/01 00:00 [pmc-release]
AID - db18-0232 [pii]
AID - 0232 [pii]
AID - 10.2337/db18-0232 [doi]
PST - ppublish
SO  - Diabetes. 2019 Jan;68(1):141-155. doi: 10.2337/db18-0232. Epub 2018 Oct 23.