Erythropoietin ameliorates the reduced migration of human fibroblasts during in vitro hypoxia.
Erythropoietin promotes the formation of granulation tissue when administered to soft tissue wounds and it was shown to be most effective under tissue hypoxia. However, the action of erythropoietin on the cellular level is not well understood. In order to get a better insight into these processes, an in vitro wound healing assay was applied. Two main players of soft tissue healing-fibroblasts and microvascular endothelial cells-were used as mono- and co-cultures, subsequently inflicting in vitro wounds. Cell migration, proliferation, the differentiation of fibroblasts to myofibroblasts, and the release of vascular endothelial cell growth factor A and angiogenin were quantified in response to hypoxia and erythropoietin (5 IU/ml). Erythropoietin supplementation did neither affect proliferation nor migration of endothelial cells and fibroblasts under normoxia. Under hypoxia, the reduced fibroblast migration was ameliorated by erythropoietin. This effect coincided with an attenuated release of vascular endothelial growth factor A, whereas angiogenin release was unaffected by erythropoietin. The in vitro model applied in this study may represent an adequate approximation to certain aspects of the in vivo status of soft tissue regeneration and the results might serve to interpret the in vivo efficiency of erythropoietin at the cellular level: Erythropoietin has different impacts on the cells in normoxia and hypoxia. Its positive influence on fibroblast migration during hypoxia seems to support the strategies of applying erythropoietin in those chronic wounds, which exhibit fibroblastic dysfunction although good vascularisation is present.
Breit
Stephanie
S
Laboratory for Molecular and Cell Biology, Department of Trauma, Hand, and Reconstructive Surgery, Saarland University, Kirrberger Strasse, Bldng. No. 57, 66421 Homburg, Germany.
Bubel
Monika
M
Pohlemann
Tim
T
Oberringer
Martin
M
D002454:Cell Differentiation; D015687:Cell Hypoxia / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D058628:Myofibroblasts / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; C046366:angiogenin; D012259:Ribonuclease, Pancreatic
Br J Haematol. 1996 Oct;95(1):27-32
8857934
J Mol Histol. 2008 Feb;39(1):37-47
17786573
Blood. 1999 Apr 15;93(8):2627-36
10194442
J Mol Neurosci. 2005;25(2):183-9
15784966
Angiology. 1997 Feb;48(2):141-7
9040269
Diabetes. 2004 Sep;53(9):2509-17
15331568
Ostomy Wound Manage. 2004 Oct;50(10):64-70
15509883
Br J Haematol. 2008 Apr;141(1):14-31
18324962
Oncogene. 2005 Jan 13;24(3):445-56
15558023
Nature. 1992 Oct 29;359(6398):843-5
1279431
Shock. 2004 Aug;22(2):169-73
15257091
Am J Physiol Cell Physiol. 2004 Feb;286(2):C416-25
14561589
Mol Cell Biol. 1996 Sep;16(9):4604-13
8756616
Proc Natl Acad Sci U S A. 1990 Aug;87(15):5978-82
2165612
J Investig Dermatol Symp Proc. 2000 Dec;5(1):40-6
11147674
Cell Death Differ. 2004 Jul;11 Suppl 1:S37-44
15243580
J Invest Dermatol. 1997 Mar;108(3):263-8
9036922
Ann Plast Surg. 1999 May;42(5):514-9; discussion 519-20
10340860
Biol Cell. 2007 Apr;99(4):197-207
17222082
FASEB J. 2006 Jan;20(1):163-5
16263938
J Cell Physiol. 1993 Mar;154(3):506-10
8436599
Acta Derm Venereol. 2002;82(6):411-7
12575845
Wound Repair Regen. 2008 Sep-Oct;16(5):585-601
19128254
Wound Repair Regen. 1996 Apr-Jun;4(2):211-8
17177815
J Am Soc Nephrol. 1998 Nov;9(11):1998-2004
9808085
Acta Neurochir (Wien). 2010 Apr;152(4):681-8
19826757
J Invest Surg. 2006 May-Jun;19(3):163-73
16809226
Genes Cells. 2002 Feb;7(2):143-9
11895478
Am J Pathol. 2003 Jan;162(1):303-12
12507913
Am J Pathol. 2003 Sep;163(3):993-1000
12937140
EMBO J. 2007 Mar 7;26(5):1221-33
17304217
Acta Biochim Biophys Sin (Shanghai). 2008 Jul;40(7):619-24
18604453
Crit Care Med. 2006 Apr;34(4):1139-46
16484928
Blood. 2004 Oct 1;104(7):2073-80
15205261
J Exp Med. 2003 Sep 15;198(6):971-5
12975460
Eur J Clin Invest. 2002 Feb;32(2):110-4
11895457
Kidney Int. 1993 May;43(5):1010-4
8510379
J Cell Physiol. 2002 Feb;190(2):259-65
11807830
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4044-9
11259643
Am J Physiol Regul Integr Comp Physiol. 2004 Jun;286(6):R977-88
15142852
Int J Low Extrem Wounds. 2003 Jun;2(2):107-20
15866835
J Pathol. 2003 Jul;200(4):500-3
12845617
Am J Physiol. 1997 May;272(5 Pt 1):C1700-8
9176162
Am J Physiol. 1999 Jul;277(1):C1-9
10409103
Histochem Cell Biol. 2005 Jun;123(6):595-603
15912358