PMID- 28276602
OWN - NLM
STAT- MEDLINE
DCOM- 20180223
LR  - 20220414
IS  - 1549-4918 (Electronic)
IS  - 1066-5099 (Print)
IS  - 1066-5099 (Linking)
VI  - 35
IP  - 6
DP  - 2017 Jun
TI  - Multifactorial Experimental Design to Optimize the Anti-Inflammatory and 
      Proangiogenic Potential of Mesenchymal Stem Cell Spheroids.
PG  - 1493-1504
LID - 10.1002/stem.2606 [doi]
AB  - Mesenchymal stem cell therapies promote wound healing by manipulating the local 
      environment to enhance the function of host cells. Aggregation of mesenchymal 
      stem cells (MSCs) into three-dimensional spheroids increases cell survival and 
      augments their anti-inflammatory and proangiogenic potential, yet there is no 
      consensus on the preferred conditions for maximizing spheroid function in this 
      application. The objective of this study was to optimize conditions for forming 
      MSC spheroids that simultaneously enhance their anti-inflammatory and 
      proangiogenic nature. We applied a design of experiments (DOE) approach to 
      determine the interaction between three input variables (number of cells per 
      spheroid, oxygen tension, and inflammatory stimulus) on MSC spheroids by 
      quantifying secretion of prostaglandin E(2) (PGE(2) ) and vascular endothelial 
      growth factor (VEGF), two potent molecules in the MSC secretome. DOE results 
      revealed that MSC spheroids formed with 40,000 cells per spheroid in 1% oxygen 
      with an inflammatory stimulus (Spheroid 1) would exhibit enhanced PGE(2) and VEGF 
      production versus those formed with 10,000 cells per spheroid in 21% oxygen with 
      no inflammatory stimulus (Spheroid 2). Compared to Spheroid 2, Spheroid 1 
      produced fivefold more PGE(2) and fourfold more VEGF, providing the opportunity 
      to simultaneously upregulate the secretion of these factors from the same 
      spheroid. The spheroids induced macrophage polarization, sprout formation with 
      endothelial cells, and keratinocyte migration in a human skin equivalent 
      model-demonstrating efficacy on three key cell types that are dysfunctional in 
      chronic non-healing wounds. We conclude that DOE-based analysis effectively 
      identifies optimal culture conditions to enhance the anti-inflammatory and 
      proangiogenic potential of MSC spheroids. Stem Cells 2017;35:1493-1504.
CI  - (c) 2017 AlphaMed Press.
FAU - Murphy, Kaitlin C
AU  - Murphy KC
AD  - Department of Biomedical Engineering, University of California Davis, Davis, 
      California, USA.
FAU - Whitehead, Jacklyn
AU  - Whitehead J
AD  - Department of Biomedical Engineering, University of California Davis, Davis, 
      California, USA.
FAU - Falahee, Patrick C
AU  - Falahee PC
AD  - Department of Biomedical Engineering, University of California Davis, Davis, 
      California, USA.
FAU - Zhou, Dejie
AU  - Zhou D
AD  - Department of Biomedical Engineering, University of California Davis, Davis, 
      California, USA.
FAU - Simon, Scott I
AU  - Simon SI
AD  - Department of Biomedical Engineering, University of California Davis, Davis, 
      California, USA.
FAU - Leach, J Kent
AU  - Leach JK
AUID- ORCID: 0000-0002-1673-3335
AD  - Department of Biomedical Engineering, University of California Davis, Davis, 
      California, USA.
AD  - Department of Orthopaedic Surgery, School of Medicine, University of California 
      Davis, Sacramento, California, USA.
LA  - eng
GR  - R01 AI047294/AI/NIAID NIH HHS/United States
GR  - R01 AI129302/AI/NIAID NIH HHS/United States
GR  - R01 DE025475/DE/NIDCR NIH HHS/United States
PT  - Journal Article
DEP - 20170327
PL  - England
TA  - Stem Cells
JT  - Stem cells (Dayton, Ohio)
JID - 9304532
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (NF-kappa B)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Anti-Inflammatory Agents/*metabolism
MH  - Cell Polarity/drug effects
MH  - Cell Size/drug effects
MH  - Cellular Microenvironment/drug effects
MH  - Colony-Forming Units Assay
MH  - Culture Media, Conditioned/pharmacology
MH  - Humans
MH  - Macrophage Activation/drug effects
MH  - Mesenchymal Stem Cells/cytology/drug effects/*metabolism
MH  - NF-kappa B/metabolism
MH  - *Neovascularization, Physiologic/drug effects
MH  - Phenotype
MH  - Reproducibility of Results
MH  - Research Design
MH  - Signal Transduction/drug effects
MH  - Skin, Artificial
MH  - Spheroids, Cellular/cytology/drug effects/*metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Wound Healing/drug effects
PMC - PMC5446296
MID - NIHMS857404
OTO - NOTNLM
OT  - Design of experiments
OT  - Inflammation
OT  - Mesenchymal stem cell
OT  - Proangiogenic
OT  - Prostaglandin E2
COIS- DISCLOSURE STATEMENT The authors indicate no potential conflicts of interest.
EDAT- 2017/03/10 06:00
MHDA- 2018/02/24 06:00
PMCR- 2018/06/01
CRDT- 2017/03/10 06:00
PHST- 2015/11/13 00:00 [received]
PHST- 2017/02/13 00:00 [revised]
PHST- 2017/02/19 00:00 [accepted]
PHST- 2017/03/10 06:00 [pubmed]
PHST- 2018/02/24 06:00 [medline]
PHST- 2017/03/10 06:00 [entrez]
PHST- 2018/06/01 00:00 [pmc-release]
AID - 10.1002/stem.2606 [doi]
PST - ppublish
SO  - Stem Cells. 2017 Jun;35(6):1493-1504. doi: 10.1002/stem.2606. Epub 2017 Mar 27.