Lactate stimulates vasculogenic stem cells via the thioredoxin system and engages an autocrine activation loop involving hypoxia-inducible factor 1.
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.
Milovanova
Tatyana N
TN
Institute for Environmental Medicine, University of Pennsylvania Medical Center, Philadelphia, PA 19104-6068, USA.
Bhopale
Veena M
VM
Sorokina
Elena M
EM
Moore
Jonni S
JS
Hunt
Thomas K
TK
Hauer-Jensen
Martin
M
Velazquez
Omaida C
OC
Thom
Stephen R
SR
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D001773:Blood Cells / Q000166:cytology / Q000187:drug effects; D001808:Blood Vessels / Q000166:cytology* / Q000187:drug effects; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D005434:Flow Cytometry; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism / Q000494:pharmacology*; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011509:Proteoglycans / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D013880:Thioredoxin-Disulfide Reductase; D013879:Thioredoxins / Q000378:metabolism*; D013997:Time Factors
D018952:Antigens, CD34; D000975:Antioxidants; D015415:Biomarkers; D004338:Drug Combinations; D051793:Hypoxia-Inducible Factor 1; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D019344:Lactic Acid; D013879:Thioredoxins; D003094:Collagen; D013880:Thioredoxin-Disulfide Reductase