title: Shock wave treatment enhances cell proliferation and improves wound healing by ATP release-coupled extracellular signal-regulated kinase (ERK) activation.
abstract: Shock wave treatment accelerates impaired wound healing in diverse clinical situations. However, the mechanisms underlying the beneficial effects of shock waves have not yet been fully revealed. Because cell proliferation is a major requirement in the wound healing cascade, we used in vitro studies and an in vivo wound healing model to study whether shock wave treatment influences proliferation by altering major extracellular factors and signaling pathways involved in cell proliferation. We identified extracellular ATP, released in an energy- and pulse number-dependent manner, as a trigger of the biological effects of shock wave treatment. Shock wave treatment induced ATP release, increased Erk1/2 and p38 MAPK activation, and enhanced proliferation in three different cell types (C3H10T1/2 murine mesenchymal progenitor cells, primary human adipose tissue-derived stem cells, and a human Jurkat T cell line) in vitro. Purinergic signaling-induced Erk1/2 activation was found to be essential for this proliferative effect, which was further confirmed by in vivo studies in a rat wound healing model where shock wave treatment induced proliferation and increased wound healing in an Erk1/2-dependent fashion. In summary, this report demonstrates that shock wave treatment triggers release of cellular ATP, which subsequently activates purinergic receptors and finally enhances proliferation in vitro and in vivo via downstream Erk1/2 signaling. In conclusion, our findings shed further light on the molecular mechanisms by which shock wave treatment exerts its beneficial effects. These findings could help to improve the clinical use of shock wave treatment for wound healing.
authors.affiliation: Department of Biochemical Engineering, University of Applied Sciences Technikum Wien, 1200 Vienna, Austria,; The Austrian Cluster for Tissue Regeneration, Vienna, Austria.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Weihs
authors.affiliation: Department of Biochemical Engineering, University of Applied Sciences Technikum Wien, 1200 Vienna, Austria,; The Austrian Cluster for Tissue Regeneration, Vienna, Austria,. Electronic address: fuchsc@technikum-wien.at.
authors.forename: Christiane
authors.initials: C
authors.lastname: Fuchs
authors.affiliation: Department of Biochemical Engineering, University of Applied Sciences Technikum Wien, 1200 Vienna, Austria,; The Austrian Cluster for Tissue Regeneration, Vienna, Austria.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Teuschl
authors.affiliation: The Austrian Cluster for Tissue Regeneration, Vienna, Austria,; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology/Austrian Workers' Compensation Board (AUVA) Research Center, 1200 Vienna, Austria.
authors.forename: Joachim
authors.initials: J
authors.lastname: Hartinger
authors.affiliation: The Austrian Cluster for Tissue Regeneration, Vienna, Austria,; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology/Austrian Workers' Compensation Board (AUVA) Research Center, 1200 Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Slezak
authors.affiliation: The Austrian Cluster for Tissue Regeneration, Vienna, Austria,; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology/Austrian Workers' Compensation Board (AUVA) Research Center, 1200 Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Mittermayr
authors.affiliation: The Austrian Cluster for Tissue Regeneration, Vienna, Austria,; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology/Austrian Workers' Compensation Board (AUVA) Research Center, 1200 Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Redl
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology/Austrian Workers' Compensation Board (AUVA) Research Center, 1200 Vienna, Austria,; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, and.
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Junger
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
authors.affiliation: Department of Biochemical Engineering, University of Applied Sciences Technikum Wien, 1200 Vienna, Austria,; The Austrian Cluster for Tissue Regeneration, Vienna, Austria.
authors.forename: Dominik
authors.initials: D
authors.lastname: Rünzler
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019220:High-Energy Shock Waves; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D014945:Wound Healing
chemical_list: D000255:Adenosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ATP; Cell Proliferation; Extracellular Signal-regulated Kinase (ERK); Shock Wave Treatment; Signal Transduction; Wound Healing