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Molecular and Cellular Biology, October 2008, p. 6248-6261, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00795-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Lactate Stimulates Vasculogenic Stem Cells via the Thioredoxin System and Engages an Autocrine Activation Loop Involving Hypoxia-Inducible Factor 1{triangledown}

Tatyana N. Milovanova,1 Veena M. Bhopale,1 Elena M. Sorokina,1 Jonni S. Moore,2 Thomas K. Hunt,3 Martin Hauer-Jensen,4 Omaida C. Velazquez,5 and Stephen R. Thom1,6*

Institute for Environmental Medicine,1 Departments of Pathology and Laboratory Medicine,2 Emergency Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104,6 Department of Surgery, University of California at San Francisco, San Francisco, California 14143,3 Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas,4 Department of Surgery, University of Miami, Miami, Florida5

Received 16 May 2008/ Returned for modification 19 June 2008/ Accepted 1 August 2008

The recruitment and differentiation of circulating stem/progenitor cells (SPCs) in subcutaneous Matrigel in mice was assessed. There were over one million CD34+ SPCs per Matrigel plug 18 h after Matrigel implantation, and including a polymer to elevate the lactate concentration increased the number of SPCs by 3.6-fold. Intricate CD34+ cell-lined channels were linked to the systemic circulation, and lactate accelerated cell differentiation as evaluated based on surface marker expression and cell cycle entry. CD34+ SPCs from lactate-supplemented Matrigel exhibited significantly higher concentrations of thioredoxin 1 (Trx1) and hypoxia-inducible factor 1 (HIF-1) than cells from unsupplemented Matrigel, whereas Trx1 and HIF-1 in CD45+ leukocytes were not elevated by lactate. Results obtained using small inhibitory RNA (siRNA) specific to HIF-1 and mice with conditionally HIF-1 null myeloid cells indicated that SPC recruitment and lactate-mediated effects were dependent on HIF-1. Cells from lactate-supplemented Matrigel had higher concentrations of phosphorylated extracellular signal-regulated kinases 1 and 2, Trx1, Trx reductase (TrxR), vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1) than cells from unsupplemented Matrigel. SPC recruitment and protein changes were inhibited by siRNA specific to lactate dehydrogenase, TrxR, or HIF-1 and by oxamate, apocynin, U0126, N-acetylcysteine, dithioerythritol, and antibodies to VEGF or SDF-1. Oxidative stress from lactate metabolism by SPCs accelerated further SPC recruitment and differentiation through Trx1-mediated elevations in HIF-1 levels and the subsequent synthesis of HIF-1-dependent growth factors.

* Corresponding author. Mailing address: Institute for Environmental Medicine, University of Pennsylvania, 1 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6068. Phone: (215) 898-9095. Fax: (215) 573-7037. E-mail: sthom{at}mail.med.upenn.edu

{triangledown} Published ahead of print on 18 August 2008.

Molecular and Cellular Biology, October 2008, p. 6248-6261, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00795-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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