title: Sources of cells that contribute to atherosclerotic intimal calcification: an in vivo genetic fate mapping study.
abstract: OBJECTIVE
  Vascular cartilaginous metaplasia and calcification are common in patients with atherosclerosis. However, sources of cells contributing to the development of this complication are currently unknown. In this study, we ascertained the origin of cells that give rise to cartilaginous and bony elements in atherosclerotic vessels.
  
  
  RESULTS
  We utilized genetic fate mapping strategies to trace cells of smooth muscle (SM) origin via SM22α-Cre recombinase and Rosa26-LacZ Cre reporter alleles. In animals expressing both transgenes, co-existence within a single cell of β-galactosidase [marking cells originally derived from SM cells (SMCs)] with osteochondrogenic (Runx2/Cbfa1) or chondrocytic (Sox9, type II collagen) markers, along with simultaneous loss of SM lineage proteins, provides a strong evidence supporting reprogramming of SMCs towards osteochondrogenic or chondrocytic differentiation. Using this technique, we found that vascular SMCs accounted for ~80% of Runx2/Cbfa1-positive cells and almost all of type II collagen-positive cells (~98%) in atherosclerotic vessels of LDLr-/- and ApoE-/- mice. We also assessed contribution from bone marrow (BM)-derived cells via analysing vessels dissected from chimerical ApoE-/- mice transplanted with green fluorescence protein-expressing BM. Marrow-derived cells were found to account for ~20% of Runx2/Cbfa1-positive cells in calcified atherosclerotic vessels of ApoE-/- mice.
  
  
  CONCLUSIONS
  Our results are the first to definitively identify cell sources attributable to atherosclerotic intimal calcification. SMCs were found to be a major contributor that reprogrammed its lineage towards osteochondrogenesis. Marrow-derived cells from the circulation also contributed significantly to the early osteochondrogenic differentiation in atherosclerotic vessels.
authors.affiliation: Department of Bioengineering,  University of Washington, Box 355061, 3720 15th Ave. NE, Foege N310D, Seattle, WA 98195,  USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Naik
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Leaf
authors.forename: Jie Hong
authors.initials: JH
authors.lastname: Hu
authors.forename: Hsueh-Ying
authors.initials: HY
authors.lastname: Yang
authors.forename: Ngoc B
authors.initials: NB
authors.lastname: Nguyen
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Giachelli
authors.forename: Mei Y
authors.initials: MY
authors.lastname: Speer
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000235:genetics*; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D002478:Cells, Cultured; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D001616:beta-Galactosidase