PMID- 29280872
OWN - NLM
STAT- MEDLINE
DCOM- 20180112
LR  - 20230812
IS  - 1529-4242 (Electronic)
IS  - 0032-1052 (Print)
IS  - 0032-1052 (Linking)
VI  - 141
IP  - 1
DP  - 2018 Jan
TI  - PHD-2 Suppression in Mesenchymal Stromal Cells Enhances Wound Healing.
PG  - 55e-67e
LID - 10.1097/PRS.0000000000003959 [doi]
AB  - BACKGROUND: Cell therapy with mesenchymal stromal cells is a promising strategy 
      for tissue repair. Restoration of blood flow to ischemic tissues is a key step in 
      wound repair, and mesenchymal stromal cells have been shown to be proangiogenic. 
      Angiogenesis is critically regulated by the hypoxia-inducible factor (HIF) 
      superfamily, consisting of transcription factors targeted for degradation by 
      prolyl hydroxylase domain (PHD)-2. The aim of this study was to enhance the 
      proangiogenic capability of mesenchymal stromal cells and to use these modified 
      cells to promote wound healing. METHODS: Mesenchymal stromal cells harvested from 
      mouse bone marrow were transduced with short hairpin RNA (shRNA) against PHD-2; 
      control cells were transduced with scrambled shRNA (shScramble) construct. Gene 
      expression quantification, human umbilical vein endothelial cell tube formation 
      assays, and wound healing assays were used to assess the effect of PHD knockdown 
      mesenchymal stromal cells on wound healing dynamics. RESULTS: PHD-2 knockdown 
      mesenchymal stromal cells overexpressed HIF-1alpha and multiple angiogenic factors 
      compared to control (p < 0.05). Human umbilical vein endothelial cells treated 
      with conditioned medium from PHD-2 knockdown mesenchymal stromal cells exhibited 
      increased formation of capillary-like structures and enhanced migration compared 
      with human umbilical vein endothelial cells treated with conditioned medium from 
      shScramble-transduced mesenchymal stromal cells (p < 0.05). Wounds treated with 
      PHD-2 knockdown mesenchymal stromal cells healed at a significantly accelerated 
      rate compared with wounds treated with shScramble mesenchymal stromal cells (p < 
      0.05). Histologic studies revealed increased blood vessel density and increased 
      cellularity in the wounds treated with PHD-2 knockdown mesenchymal stromal cells 
      (p < 0.05). CONCLUSIONS: Silencing PHD-2 in mesenchymal stromal cells augments 
      their proangiogenic potential in wound healing therapy. This effect appears to be 
      mediated by overexpression of HIF family transcription factors and up-regulation 
      of multiple downstream angiogenic factors.
FAU - Ko, Sae Hee
AU  - Ko SH
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Nauta, Allison C
AU  - Nauta AC
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Morrison, Shane D
AU  - Morrison SD
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Hu, Michael S
AU  - Hu MS
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Zimmermann, Andrew S
AU  - Zimmermann AS
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Chung, Michael T
AU  - Chung MT
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Glotzbach, Jason P
AU  - Glotzbach JP
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Wong, Victor W
AU  - Wong VW
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Walmsley, Graham G
AU  - Walmsley GG
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Peter Lorenz, H
AU  - Peter Lorenz H
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Chan, Denise A
AU  - Chan DA
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Gurtner, Geoffrey C
AU  - Gurtner GC
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Giaccia, Amato J
AU  - Giaccia AJ
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
FAU - Longaker, Michael T
AU  - Longaker MT
AD  - Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, 
      N.Y.
AD  - From the Hagey Laboratory for Regenerative Medicine, Division of Plastic and 
      Reconstructive Surgery, Department of Surgery, the Department of Radiation 
      Oncology, and the Institute of Stem Cell Biology and Regenerative Medicine, 
      Stanford University School of Medicine; the Division of Vascular Surgery, 
      Department of Surgery, University of California, San Diego; the Division of 
      Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and 
      Sciences University; the Division of Cardiothoracic Surgery, Department of 
      Surgery, New York Presbyterian Hospital; and the Department of Radiation 
      Oncology, University of California, San Francisco.
LA  - eng
GR  - R01 GM087609/GM/NIGMS NIH HHS/United States
GR  - U01 HL099776/HL/NHLBI NIH HHS/United States
GR  - R00 AG049958/AG/NIA NIH HHS/United States
GR  - R56 DK074095/DK/NIDDK NIH HHS/United States
GR  - R01 DE019434/DE/NIDCR NIH HHS/United States
GR  - R01 DE021683/DE/NIDCR NIH HHS/United States
GR  - R01 DK074095/DK/NIDDK NIH HHS/United States
GR  - R01 CA088480/CA/NCI NIH HHS/United States
GR  - R37 CA088480/CA/NCI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Plast Reconstr Surg
JT  - Plastic and reconstructive surgery
JID - 1306050
RN  - 0 (Biomarkers)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 1.14.11.29 (Egln1 protein, mouse)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
SB  - IM
MH  - Animals
MH  - Biomarkers/metabolism
MH  - Blotting, Western
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Gene Knockdown Techniques
MH  - *Gene Silencing
MH  - Human Umbilical Vein Endothelial Cells/physiology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases/*genetics
MH  - Male
MH  - *Mesenchymal Stem Cell Transplantation
MH  - Mesenchymal Stem Cells/*physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neovascularization, Physiologic/*physiology
MH  - Random Allocation
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Up-Regulation
MH  - Wound Healing/*physiology
PMC - PMC5747314
MID - NIHMS902095
EDAT- 2017/12/28 06:00
MHDA- 2018/01/13 06:00
PMCR- 2019/01/01
CRDT- 2017/12/28 06:00
PHST- 2017/12/28 06:00 [entrez]
PHST- 2017/12/28 06:00 [pubmed]
PHST- 2018/01/13 06:00 [medline]
PHST- 2019/01/01 00:00 [pmc-release]
AID - 00006534-201801000-00024 [pii]
AID - 10.1097/PRS.0000000000003959 [doi]
PST - ppublish
SO  - Plast Reconstr Surg. 2018 Jan;141(1):55e-67e. doi: 10.1097/PRS.0000000000003959.