Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease.
Mesenchymal stem cell (MSC)-like cells reside in the vascular wall, but their role in vascular regeneration and disease is poorly understood. Here, we show that Gli1+cells located in the arterial adventitia are progenitors of vascular smooth muscle cells and contribute to neointima formation and repair after acute injury to the femoral artery. Genetic fate tracing indicates that adventitial Gli1+MSC-like cells migrate into the media and neointima during athero- and arteriosclerosis in ApoE-/-mice with chronic kidney disease. Our data indicate that Gli1+cells are a major source of osteoblast-like cells during calcification in the media and intima. Genetic ablation of Gli1+cells before induction of kidney injury dramatically reduced the severity of vascular calcification. These findings implicate Gli1+cells as critical adventitial progenitors in vascular remodeling after acute and during chronic injury and suggest that they may be relevant therapeutic targets for mitigation of vascular calcification.
Division of Nephrology and Clinical Immunology, Medical Faculty RWTH Aachen University, RWTH Aachen University, 52074 Aachen, Germany; Renal Division, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02138, USA. Electronic address: rkramann@gmx.net.
Rafael
R
Kramann
Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Claudia
C
Goettsch
Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Janewit
J
Wongboonsin
Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Hiroshi
H
Iwata
Division of Hematology, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02138, USA; Division of Hematology, RWTH Aachen University, 52074 Aachen, Germany.
Rebekka K
RK
Schneider
Division of Nephrology and Clinical Immunology, Medical Faculty RWTH Aachen University, RWTH Aachen University, 52074 Aachen, Germany.
Christoph
C
Kuppe
Division of Nephrology and Clinical Immunology, Medical Faculty RWTH Aachen University, RWTH Aachen University, 52074 Aachen, Germany.
Nadine
N
Kaesler
Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Monica
M
Chang-Panesso
Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Flavia G
FG
Machado
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Susannah
S
Gratwohl
Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kaushal
K
Madhurima
Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Joshua D
JD
Hutcheson
Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Sanjay
S
Jain
Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA; Center for Excellence in Vascular Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02138, USA.
Elena
E
Aikawa
Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Benjamin D
BD
Humphreys
D063194:Adventitia / Q000473:pathology*; D000368:Aged; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000067696:Ataxin-1 / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D054337:Cell Dedifferentiation; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D058426:Neointima / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000473:pathology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000473:pathology; D013234:Stem Cells / Q000473:pathology*; D061205:Vascular Calcification / Q000150:complications* / Q000473:pathology; D066253:Vascular Remodeling; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism
D018952:Antigens, CD34; D000067696:Ataxin-1; D015415:Biomarkers; C400551:GLI1 protein, human; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C509239:SHH protein, human; D000071676:Zinc Finger Protein GLI1; D020797:Receptor, Platelet-Derived Growth Factor beta