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Explicit Evidence of Smooth Muscle Cell Transdifferentiation in Calcifying Blood Vessels: an In Vivo Lineage Tracing Study using Matrix Gla Protein Knockout Mice
Author(s) -
Speer Mei Y.,
Yang HsuehYing,
Look Amy,
Lin WeiLing M,
Frutkin Andrew,
Dichek David,
Giachelli Cecelia M
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.49.10
Subject(s) - transdifferentiation , myocardin , calcification , matrix gla protein , biology , cre recombinase , microbiology and biotechnology , runx2 , pathology , genetically modified mouse , transgene , endocrinology , genetics , stem cell , medicine , transcription factor , ectopic calcification , gene , serum response factor
Vascular calcification is a major risk factor for cardiovascular morbidity and mortality. In order to develop appropriate prophylactic and therapeutic strategies, it is important to understand the origins of the cells that participate in this process. In this study, we crossed matrix Gla protein null mice (MGP−/−) that spontaneously develop vascular calcification with mice carrying SM22α‐Cre recombinase and Rosa26‐LacZ Cre reporter transgenes. Thus, cells of SM lineage were genetically traced by their ability to express β‐galactosidase irrespective of subsequent SMC lineage protein expression. Co‐localization of within a single cell of β‐galactosidase with the loss of SM lineage markers and the gain of osteochondrogenic and chondrocytic markers identified transdifferentiation of SMCs to osteochondrogenic precursors or chondrocytes. Furthermore, transdifferentiation of SMCs occurred prior to calcium deposition, and was associated with an early onset of Runx2/Cbfa1 expression and the down regulation of myocardin and Msx2. There was no change in the constitutive expression of Sox9 or BMP2. Osterix, Wnt3a and Wnt7a were not detected. These results are the first to definitively demonstrate transdifferentiation of adult SMCs and indicate that SMC transdifferentiation is an important process driving calcification as well as the appearance of skeletal elements in calcified vascular lesions.