Sca-1+ progenitor cells in the adult mouse aorta are known to generate vascular smooth muscle cells (VSMCs), but their embryological origins and temporal abundance are not known. Using tamoxifen-inducible Myf5-CreER mice, we demonstrate that Sca-1+ adult aortic cells arise from the somitic mesoderm beginning at E8.5 and continue throughout somitogenesis. Myf5 lineage-derived Sca-1+ cells greatly expand in situ, starting at 4 weeks of age, and become a major source of aortic Sca-1+ cells by 6 weeks of age. Myf5-derived adult aortic cells are capable of forming multicellular sphere-like structures in vitro and express the pluripotency marker Sox2. Exposure to transforming growth factor-β3 induces these spheres to differentiate into calponin-expressing VSMCs. Pulse-chase experiments using tamoxifen-inducible Sox2-CreERT2 mice at 8 weeks of age demonstrate that ∼35% of all adult aortic Sca-1+ cells are derived from Sox2+ cells. The present study demonstrates that aortic Sca-1+ progenitor cells are derived from the somitic mesoderm formed at the earliest stages of somitogenesis and from Sox2-expressing progenitors in adult mice.
Get full access to this article
View all access options for this article.
References
1.
AsaharaT, MuroharaT, SullivanA, SilverM, van der ZeeR, LiT, WitzenbichlerB, SchattemanG and IsnerJM. (1997). Isolation of putative progenitor endothelial cells for angiogenesis. Science, 275:964–966.
2.
BiancoP, RobeyPG and SimmonsPJ. (2008). Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell, 2:313–319.
3.
HuY, ZhangZ, TorsneyE, AfzalAR, DavisonF, MetzlerB and XuQ. (2004). Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest, 113:1258–1265.
4.
DanielJ-M, BielenbergW, StiegerP, WeinertS, TillmannsH and SeddingDG. (2010). Time-course analysis on the differentiation of bone marrow-derived progenitor cells Into smooth muscle cells During neointima formation. Arterioscler Thromb Vasc Biol, 30:1890–1896.
5.
PassmanJN, DongXR, WuS-P, MaguireCT, HoganKA, BautchVL and MajeskyMW. (2008). A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells. Proc Natl Acad Sci U S A, 105:9349–9354.
6.
ShikataniEA, ChandyM, BeslaR, LiCC, MomenA, El-MounayriO, RobbinsCS and HusainM. (2016). c-Myb Regulates Proliferation and Differentiation of Adventitial Sca1 + vascular smooth muscle cell Progenitors by Transactivation of myocardin. Arterioscler Thromb Vasc Biol, 36:1367–1376.
ResendeTP, FerreiraM, TeilletM-A, TavaresAT, AndradeRP and PalmeirimI. (2010). Sonic hedgehog in temporal control of somite formation. Proc Natl Acad Sci U S A, 107:12907–12912.
9.
OttM-O, BoberE, LyonsG, ArnoldH and BuckinghamM. (1991). Early expression of the myogenic regulatory gene myf-5 in precursor cells of skeletal muscle in the mouse embryo. Development, 111:1097–1107.
10.
BiressiS, BjornsonCRR, CarligPMM, NishijoK, KellerC and RandoTA. (2013). Myf5 expression during fetal myogenesis defines the developmental progenitors of adult satellite cells. Dev Biol, 379:195–207.
11.
JinnoH, MorozovaO, JonesKL, BiernaskieJA, ParisM, HosokawaR, RudnickiMA, ChaiY, RossiF. (2010). Convergent genesis of an adult neural crest-like dermal stem cell from distinct developmental origins. Stem Cells, 28:2027–2040.
12.
MadisenL, ZwingmanTA, SunkinSM, OhSW, ZariwalaHA, GuH, NgLL, PalmiterRD, HawrylyczMJ, et al. (2010). A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci, 13:133–140.
13.
ArnoldK, SarkarA, YramMA, PoloJM, BronsonR, SenguptaS, SeandelM, GeijsenN and HochedlingerK. (2011). Sox2 + adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell, 9:317–329.
14.
SorianoP. (1999). Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet, 21:70–71.
15.
SamokhvalovIM, SamokhvalovaNI and NishikawaSI. (2007). Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature, 446:1056–1061.
16.
ButcherMJ, HerreM, LeyK and GalkinaE. (2011). Flow cytometry analysis of immune cells within murine aortas. J Vis Exp, 53: pii: 2848.
17.
GalkinaE, KadlA, SandersJ, VarugheseD, SarembockIJ and LeyK. (2006). Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent. J Exp Med, 203:1273–1282.
18.
CornwellTL and LincolnTM. (1989). Regulation of intracellular Ca2+ levels in cultured vascular smooth muscle cells. Reduction of Ca2+ by atriopeptin and 8-bromo-cyclic GMP is mediated by cyclic GMP-dependent protein kinase. J Biol Chem, 264:1146–1155.
19.
PsaltisPJ, HarbuzariuA, DelacroixS, WittTA, HolroydEW, SpoonDB, HoffmanSJ, PanS, KleppeLS, et al. (2012). Identification of a monocyte-predisposed hierarchy of hematopoietic progenitor cells in the adventitia of postnatal murine aorta. Circulation, 125:592–603.
20.
PsaltisPJ, PuranikAS, SpoonDB, ChueCD, HoffmanSJ, WittTA, DelacroixS, KleppeLS, MueskeCS, et al. (2014). Characterization of a resident population of adventitial macrophage progenitor cells in postnatal vasculature. Circ Res, 115:364–375.
21.
SteinbachSK, El-MounayriO, DacostaRS, FrontiniMJ, NongZ, MaedaA, PickeringJG, MillerFD and HusainM. (2011). Directed differentiation of skin-derived precursors into functional vascular smooth muscle cells. Arterioscler Thromb Vasc Biol, 31:2938–2948.
22.
TamPPL. (1981). The control of somitogenesis in mouse embryos. J Embryol Exp Morphol, 65(Suppl):103–128.
23.
AvilionAA, NicolisSK, PevnyLH, PerezL, VivianN and Lovell-BadgeR. (2003). Multipotent cell lineages in early mouse development on SOX2 function. Genes Dev, 17:126–140.
24.
DuKL, IpHS, LiJ, ChenM, DandreF, YuW, LuMM, OwensGK, MichaelS and ParmacekMS. (2003). Myocardin is a critical serum response factor cofactor in the transcriptional program regulating smooth muscle cell differentiation. Mol Cell Biol, 23:2425–2437.
25.
ComaiG and TajbakhshS. (2014). Molecular and cellular regulation of skeletal myogenesis. Curr Top Dev Biol, 110:1–73.
26.
TajbakhshS and SpörleR. (1998). Somite development: constructing the vertebrate body. Cell, 92:9–16.
27.
EsnerM, MeilhacSM, RelaixF, NicolasJ-F, CossuG and BuckinghamME. (2006). Smooth muscle of the dorsal aorta shares a common clonal origin with skeletal muscle of the myotome. Development, 133:737–749.
28.
Mayeuf-LouchartA, LaghaM, DanckaertA, RocancourtD, RelaixF, VincentSD and BuckinghamM. (2014). Notch regulation of myogenic versus endothelial fates of cells that migrate from the somite to the limb. Proc Natl Acad Sci U S A, 111:8844–8849.
29.
MajeskyMW, HoritaH, OstrikerA, LuS, ReganJN, BagchiA, DongXR, PoczobuttJ, NemenoffRA and Weiser-EvansMCM. (2017). Differentiated smooth muscle cells generate a subpopulation of resident vascular progenitor cells in the adventitia regulated by Klf4. Circ Res, 120:296–311.
KawaseY, YanagiY, TakatoT, FujimotoM and OkochiH. (2004). Characterization of multipotent adult stem cells from the skin: transforming growth factor-β (TGF-β) facilitates cell growth. Exp Cell Res, 295:194–203.
32.
HuberTL, KouskoffV, FehlingJJ, PalisJ and KellerG. (2004). Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature, 432:625–630.
33.
EpelmanS, LavineKJ, BeaudinAE, SojkaDK, CarreroJA, CalderonB, BrijaT, GautierEL, IvanovS, et al. (2014). Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity, 40:91–104.
34.
OwensGK. (1995). Regulation of differentiation of vascular smooth muscle cells. Physiol Rev, 75:487–517.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
