Downregulation of metabolic activity increases cell survival under hypoxic conditions: Potential applications for tissue engineering

Jaehyun Kim, Karl Erik Andersson, John D. Jackson, Sang Jin Lee, Anthony Atala, James J. Yoo

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

A major challenge to the success of cell-based implants for tissue regeneration is an insufficient supply of oxygen before host vasculature is integrated into the implants, resulting in premature cell death and dysfunction. Whereas increasing oxygenation to the implants has been a major focus in the field, our strategy is aimed at lowering oxygen consumption by downregulating cellular metabolism of cell-based implants. Adenosine, which is a purine nucleoside that functions as an energy transferring molecule, has been reported to increase under hypoxia, resulting in reducing the adenosine triphosphate (ATP) demands of the Na+/K+ ATPase. In the present study, we investigated whether adenosine could be used to downregulate cellular metabolism to achieve prolonged survival under hypoxic conditions. Murine myoblasts (C2C12) lacking a self-survival mechanism were treated with adenosine under 0.1% hypoxic stress. The cells, cultured in the presence of 5mM adenosine, maintained their viability under hypoxia, and regained their normal growth and function of forming myotubes when transferred to normoxic conditions at day 11 without further supply of adenosine, whereas nontreated cells failed to survive. An increase in adenosine concentrations shortened the onset of reproliferation after transfer to normoxic conditions. This increase correlated with an increase in metabolic downregulation during the early phase of hypoxia. A higher intracellular ATP level was observed in adenosine-treated cells throughout the duration of hypoxia. This strategy of increasing cell survival under hypoxic conditions through downregulating cellular metabolism may be utilized for cell-based tissue regeneration applications as well as protecting tissues against hypoxic injuries.

Original languageEnglish
Pages (from-to)2265-2272
Number of pages8
JournalTissue Engineering - Part A
Volume20
Issue number15-16
DOIs
StatePublished - Aug 1 2014
Externally publishedYes

Fingerprint

Bioelectric potentials
Tissue Engineering
Tissue engineering
Metabolism
Adenosine
Tissue regeneration
Cell Survival
Down-Regulation
Cells
Oxygen
Oxygenation
Cell death
Regeneration
Tissue
Adenosine Triphosphate
Molecules
Purine Nucleosides
Premature Mortality
Myoblasts
Skeletal Muscle Fibers

ASJC Scopus subject areas

  • Bioengineering
  • Biochemistry
  • Biomedical Engineering
  • Biomaterials

Cite this

Downregulation of metabolic activity increases cell survival under hypoxic conditions : Potential applications for tissue engineering. / Kim, Jaehyun; Andersson, Karl Erik; Jackson, John D.; Lee, Sang Jin; Atala, Anthony; Yoo, James J.

In: Tissue Engineering - Part A, Vol. 20, No. 15-16, 01.08.2014, p. 2265-2272.

Research output: Contribution to journalArticle

Kim, Jaehyun ; Andersson, Karl Erik ; Jackson, John D. ; Lee, Sang Jin ; Atala, Anthony ; Yoo, James J. / Downregulation of metabolic activity increases cell survival under hypoxic conditions : Potential applications for tissue engineering. In: Tissue Engineering - Part A. 2014 ; Vol. 20, No. 15-16. pp. 2265-2272.
@article{fe79c10e541a4dcf9e9779eae7c9cfe3,
title = "Downregulation of metabolic activity increases cell survival under hypoxic conditions: Potential applications for tissue engineering",
abstract = "A major challenge to the success of cell-based implants for tissue regeneration is an insufficient supply of oxygen before host vasculature is integrated into the implants, resulting in premature cell death and dysfunction. Whereas increasing oxygenation to the implants has been a major focus in the field, our strategy is aimed at lowering oxygen consumption by downregulating cellular metabolism of cell-based implants. Adenosine, which is a purine nucleoside that functions as an energy transferring molecule, has been reported to increase under hypoxia, resulting in reducing the adenosine triphosphate (ATP) demands of the Na+/K+ ATPase. In the present study, we investigated whether adenosine could be used to downregulate cellular metabolism to achieve prolonged survival under hypoxic conditions. Murine myoblasts (C2C12) lacking a self-survival mechanism were treated with adenosine under 0.1{\%} hypoxic stress. The cells, cultured in the presence of 5mM adenosine, maintained their viability under hypoxia, and regained their normal growth and function of forming myotubes when transferred to normoxic conditions at day 11 without further supply of adenosine, whereas nontreated cells failed to survive. An increase in adenosine concentrations shortened the onset of reproliferation after transfer to normoxic conditions. This increase correlated with an increase in metabolic downregulation during the early phase of hypoxia. A higher intracellular ATP level was observed in adenosine-treated cells throughout the duration of hypoxia. This strategy of increasing cell survival under hypoxic conditions through downregulating cellular metabolism may be utilized for cell-based tissue regeneration applications as well as protecting tissues against hypoxic injuries.",
author = "Jaehyun Kim and Andersson, {Karl Erik} and Jackson, {John D.} and Lee, {Sang Jin} and Anthony Atala and Yoo, {James J.}",
year = "2014",
month = "8",
day = "1",
doi = "10.1089/ten.tea.2013.0637",
language = "English",
volume = "20",
pages = "2265--2272",
journal = "Tissue Engineering - Part A",
issn = "1937-3341",
publisher = "Mary Ann Liebert Inc.",
number = "15-16",

}

TY - JOUR

T1 - Downregulation of metabolic activity increases cell survival under hypoxic conditions

T2 - Potential applications for tissue engineering

AU - Kim, Jaehyun

AU - Andersson, Karl Erik

AU - Jackson, John D.

AU - Lee, Sang Jin

AU - Atala, Anthony

AU - Yoo, James J.

PY - 2014/8/1

Y1 - 2014/8/1

N2 - A major challenge to the success of cell-based implants for tissue regeneration is an insufficient supply of oxygen before host vasculature is integrated into the implants, resulting in premature cell death and dysfunction. Whereas increasing oxygenation to the implants has been a major focus in the field, our strategy is aimed at lowering oxygen consumption by downregulating cellular metabolism of cell-based implants. Adenosine, which is a purine nucleoside that functions as an energy transferring molecule, has been reported to increase under hypoxia, resulting in reducing the adenosine triphosphate (ATP) demands of the Na+/K+ ATPase. In the present study, we investigated whether adenosine could be used to downregulate cellular metabolism to achieve prolonged survival under hypoxic conditions. Murine myoblasts (C2C12) lacking a self-survival mechanism were treated with adenosine under 0.1% hypoxic stress. The cells, cultured in the presence of 5mM adenosine, maintained their viability under hypoxia, and regained their normal growth and function of forming myotubes when transferred to normoxic conditions at day 11 without further supply of adenosine, whereas nontreated cells failed to survive. An increase in adenosine concentrations shortened the onset of reproliferation after transfer to normoxic conditions. This increase correlated with an increase in metabolic downregulation during the early phase of hypoxia. A higher intracellular ATP level was observed in adenosine-treated cells throughout the duration of hypoxia. This strategy of increasing cell survival under hypoxic conditions through downregulating cellular metabolism may be utilized for cell-based tissue regeneration applications as well as protecting tissues against hypoxic injuries.

AB - A major challenge to the success of cell-based implants for tissue regeneration is an insufficient supply of oxygen before host vasculature is integrated into the implants, resulting in premature cell death and dysfunction. Whereas increasing oxygenation to the implants has been a major focus in the field, our strategy is aimed at lowering oxygen consumption by downregulating cellular metabolism of cell-based implants. Adenosine, which is a purine nucleoside that functions as an energy transferring molecule, has been reported to increase under hypoxia, resulting in reducing the adenosine triphosphate (ATP) demands of the Na+/K+ ATPase. In the present study, we investigated whether adenosine could be used to downregulate cellular metabolism to achieve prolonged survival under hypoxic conditions. Murine myoblasts (C2C12) lacking a self-survival mechanism were treated with adenosine under 0.1% hypoxic stress. The cells, cultured in the presence of 5mM adenosine, maintained their viability under hypoxia, and regained their normal growth and function of forming myotubes when transferred to normoxic conditions at day 11 without further supply of adenosine, whereas nontreated cells failed to survive. An increase in adenosine concentrations shortened the onset of reproliferation after transfer to normoxic conditions. This increase correlated with an increase in metabolic downregulation during the early phase of hypoxia. A higher intracellular ATP level was observed in adenosine-treated cells throughout the duration of hypoxia. This strategy of increasing cell survival under hypoxic conditions through downregulating cellular metabolism may be utilized for cell-based tissue regeneration applications as well as protecting tissues against hypoxic injuries.

UR - http://www.scopus.com/inward/record.url?scp=84906533416&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906533416&partnerID=8YFLogxK

U2 - 10.1089/ten.tea.2013.0637

DO - 10.1089/ten.tea.2013.0637

M3 - Article

C2 - 24524875

AN - SCOPUS:84906533416

VL - 20

SP - 2265

EP - 2272

JO - Tissue Engineering - Part A

JF - Tissue Engineering - Part A

SN - 1937-3341

IS - 15-16

ER -