Differentiated Smooth Muscle Cells Generate a Subpopulation of Resident Vascular Progenitor Cells in the Adventitia Regulated by Klf4.
BACKGROUND
The vascular adventitia is a complex layer of the vessel wall consisting of vasa vasorum microvessels, nerves, fibroblasts, immune cells, and resident progenitor cells. Adventitial progenitors express the stem cell markers, Sca1 and CD34 (adventitial sca1-positive progenitor cells [AdvSca1]), have the potential to differentiate in vitro into multiple lineages, and potentially contribute to intimal lesions in vivo.


OBJECTIVE
Although emerging data support the existence of AdvSca1 cells, the goal of this study was to determine their origin, degree of multipotency and heterogeneity, and contribution to vessel remodeling.


RESULTS
Using 2 in vivo fate-mapping approaches combined with a smooth muscle cell (SMC) epigenetic lineage mark, we report that a subpopulation of AdvSca1 cells is generated in situ from differentiated SMCs. Our data establish that the vascular adventitia contains phenotypically distinct subpopulations of progenitor cells expressing SMC, myeloid, and hematopoietic progenitor-like properties and that differentiated SMCs are a source to varying degrees of each subpopulation. SMC-derived AdvSca1 cells exhibit a multipotent phenotype capable of differentiating in vivo into mature SMCs, resident macrophages, and endothelial-like cells. After vascular injury, SMC-derived AdvSca1 cells expand in number and are major contributors to adventitial remodeling. Induction of the transcription factor Klf4 in differentiated SMCs is essential for SMC reprogramming in vivo, whereas in vitro approaches demonstrate that Klf4 is essential for the maintenance of the AdvSca1 progenitor phenotype.


CONCLUSIONS
We propose that generation of resident vascular progenitor cells from differentiated SMCs is a normal physiological process that contributes to the vascular stem cell pool and plays important roles in arterial homeostasis and disease.
From the Division of Renal Diseases and Hypertension (H.H., A.O., S.L., A.B., J.P., R.A.N., M.C.M.W.-E.) and Cardiovascular Pulmonary Research Program, Division of Cardiology (R.A.N., M.C.M.W.-E.), School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado, Aurora (M.C.M.W.-E.); Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis (J.N.R.); Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, WA (M.W.M., X.R.D.); and Department of Pediatrics and Department of Pathology, University of Washington, Seattle (M.W.M.). mary.weiser@ucdenver.edu mwm84@uw.edu.
Mark W
MW
Majesky
From the Division of Renal Diseases and Hypertension (H.H., A.O., S.L., A.B., J.P., R.A.N., M.C.M.W.-E.) and Cardiovascular Pulmonary Research Program, Division of Cardiology (R.A.N., M.C.M.W.-E.), School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado, Aurora (M.C.M.W.-E.); Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis (J.N.R.); Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, WA (M.W.M., X.R.D.); and Department of Pediatrics and Department of Pathology, University of Washington, Seattle (M.W.M.).
Henrick
H
Horita
From the Division of Renal Diseases and Hypertension (H.H., A.O., S.L., A.B., J.P., R.A.N., M.C.M.W.-E.) and Cardiovascular Pulmonary Research Program, Division of Cardiology (R.A.N., M.C.M.W.-E.), School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado, Aurora (M.C.M.W.-E.); Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis (J.N.R.); Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, WA (M.W.M., X.R.D.); and Department of Pediatrics and Department of Pathology, University of Washington, Seattle (M.W.M.).
Allison
A
Ostriker
From the Division of Renal Diseases and Hypertension (H.H., A.O., S.L., A.B., J.P., R.A.N., M.C.M.W.-E.) and Cardiovascular Pulmonary Research Program, Division of Cardiology (R.A.N., M.C.M.W.-E.), School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado, Aurora (M.C.M.W.-E.); Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis (J.N.R.); Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, WA (M.W.M., X.R.D.); and Department of Pediatrics and Department of Pathology, University of Washington, Seattle (M.W.M.).
Sizhao
S
Lu
From the Division of Renal Diseases and Hypertension (H.H., A.O., S.L., A.B., J.P., R.A.N., M.C.M.W.-E.) and Cardiovascular Pulmonary Research Program, Division of Cardiology (R.A.N., M.C.M.W.-E.), School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado, Aurora (M.C.M.W.-E.); Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis (J.N.R.); Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, WA (M.W.M., X.R.D.); and Department of Pediatrics and Department of Pathology, University of Washington, Seattle (M.W.M.).
Jenna N
JN
Regan
From the Division of Renal Diseases and Hypertension (H.H., A.O., S.L., A.B., J.P., R.A.N., M.C.M.W.-E.) and Cardiovascular Pulmonary Research Program, Division of Cardiology (R.A.N., M.C.M.W.-E.), School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado, Aurora (M.C.M.W.-E.); Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis (J.N.R.); Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, WA (M.W.M., X.R.D.); and Department of Pediatrics and Department of Pathology, University of Washington, Seattle (M.W.M.).
Ashim
A
Bagchi
From the Division of Renal Diseases and Hypertension (H.H., A.O., S.L., A.B., J.P., R.A.N., M.C.M.W.-E.) and Cardiovascular Pulmonary Research Program, Division of Cardiology (R.A.N., M.C.M.W.-E.), School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado, Aurora (M.C.M.W.-E.); Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis (J.N.R.); Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, WA (M.W.M., X.R.D.); and Department of Pediatrics and Department of Pathology, University of Washington, Seattle (M.W.M.).
Xiu Rong
XR
Dong
From the Division of Renal Diseases and Hypertension (H.H., A.O., S.L., A.B., J.P., R.A.N., M.C.M.W.-E.) and Cardiovascular Pulmonary Research Program, Division of Cardiology (R.A.N., M.C.M.W.-E.), School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado, Aurora (M.C.M.W.-E.); Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis (J.N.R.); Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, WA (M.W.M., X.R.D.); and Department of Pediatrics and Department of Pathology, University of Washington, Seattle (M.W.M.).
Joanna
J
Poczobutt
From the Division of Renal Diseases and Hypertension (H.H., A.O., S.L., A.B., J.P., R.A.N., M.C.M.W.-E.) and Cardiovascular Pulmonary Research Program, Division of Cardiology (R.A.N., M.C.M.W.-E.), School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado, Aurora (M.C.M.W.-E.); Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis (J.N.R.); Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, WA (M.W.M., X.R.D.); and Department of Pediatrics and Department of Pathology, University of Washington, Seattle (M.W.M.).
Raphael A
RA
Nemenoff
From the Division of Renal Diseases and Hypertension (H.H., A.O., S.L., A.B., J.P., R.A.N., M.C.M.W.-E.) and Cardiovascular Pulmonary Research Program, Division of Cardiology (R.A.N., M.C.M.W.-E.), School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado, Aurora (M.C.M.W.-E.); Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis (J.N.R.); Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, WA (M.W.M., X.R.D.); and Department of Pediatrics and Department of Pathology, University of Washington, Seattle (M.W.M.). mary.weiser@ucdenver.edu mwm84@uw.edu.
Mary C M
MC
Weiser-Evans
D063194:Adventitia / Q000166:cytology* / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D011247:Pregnancy; D013234:Stem Cells / Q000502:physiology*
C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors
adventitia; smooth muscle cells; vascular remodeling