Proliferation and differentiation of smooth muscle cell precursors occurs simultaneously during the development of the vessel wall

Lee, Sang Hoon; Hungerford, Jill E.; Little, Charles D.; Iruela‐Arispe, M. Luisa

doi:10.1002/(sici)1097-0177(199708)209:4<342::aid-aja2>3.0.co;2-i

Cited by 44 publications

(26 citation statements)

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“…Calponin, which is thought to characterize cells undergoing differentiation toward a smooth muscle cell fate, was similarly expressed in P4 1 4 and P8 lungs when compared with P4. a-SMA staining appeared to be similar at all time points as well (24,25). a-SMA is found in many contractile cell types, and was observed to be localized to myofibroblasts in the tips of growing alveolar septa in the cultured and uncultured lungs (arrows, Figure 4A) (26).…”

Section: Cell Proliferation and Differentiation Continue In Cultured mentioning

confidence: 68%

A Novel In Vitro Model to Study Alveologenesis

Pieretti¹,

Ahmed

Roberts

et al. 2014

Am J Respir Cell Mol Biol

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Many pediatric pulmonary diseases are associated with significant morbidity and mortality due to impairment of alveolar development. The lack of an appropriate in vitro model system limits the identification of therapies aimed at improving alveolarization. Herein, we characterize an ex vivo lung culture model that facilitates investigation of signaling pathways that influence alveolar septation. Postnatal Day 4 (P4) mouse pup lungs were inflated with 0.4% agarose, sliced, and cultured within a collagen matrix in medium that was optimized to support cell proliferation and promote septation. Lung slices were grown with and without 1D11, an active transforming growth factor-b-neutralizing antibody. After 4 days, the lung sections (designated P4 1 4) and noncultured lung sections were examined using quantitative morphometry to assess alveolar septation and immunohistochemistry to evaluate cell proliferation and differentiation. We observed that the P4 1 4 lung sections exhibited ex vivo alveolarization, as evidenced by an increase in septal density, thinning of septal walls, and a decrease in mean linear intercept comparable to P8, age-matched, uncultured lungs. Moreover, immunostaining showed ongoing cell proliferation and differentiation in cultured lungs that were similar to P8 controls. Cultured lungs exposed to 1D11 had a distinct phenotype of decreased septal density when compared with untreated P4 1 4 lungs, indicating the utility of investigating signaling in these lung slices. These results indicate that this novel lung culture system is optimized to permit the investigation of pathways involved in septation, and potentially the identification of therapeutic targets that enhance alveolarization.

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Section: Cell Proliferation and Differentiation Continue In Cultured mentioning

confidence: 68%

A Novel In Vitro Model to Study Alveologenesis

Pieretti¹,

Ahmed

Roberts

et al. 2014

Am J Respir Cell Mol Biol

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“…First, during late embryogenesis and postnatal development, SMCs exhibit an extremely high rate of proliferation, yet at the same time, they undergo the most rapid rate of induction of expression of SMC differentiation markers in the rat and chicken aorta. 1,23 Second, PDGF-BB-induced suppression of SMC differentiation markers has been shown to be independent of its mitogenic effect. 24 Indeed, daily pulsing treatment with PDGF-BB in postconfluent culture of SMCs caused a sustained decrease in expression of SMC differentiation markers in spite of the absence of sustained mitosis.…”

Section: Discussionmentioning

confidence: 99%

Conditional Deletion of Krüppel-Like Factor 4 Delays Downregulation of Smooth Muscle Cell Differentiation Markers but Accelerates Neointimal Formation Following Vascular Injury

Yoshida

Kaestner

Owens

2008

Circulation Research

221

293

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Abstract-Phenotypic switching of smooth muscle cells (SMCs) plays a key role in vascular proliferative diseases. We previously showed that Krüppel-like factor 4 (Klf4) suppressed SMC differentiation markers in cultured SMCs. Here, we derive mice deficient for Klf4 by conditional gene ablation and analyze their vascular phenotype following carotid injury. Klf4 expression was rapidly induced in SMCs of control mice after vascular injury but not in Klf4-deficient mice. Injury-induced repression of SMC differentiation markers was transiently delayed in Klf4-deficient mice. Klf4 mutant mice exhibited enhanced neointimal formation in response to vascular injury caused by increased cellular proliferation in the media but not an altered apoptotic rate. Consistent with these findings, cultured SMCs overexpressing Klf4 showed reduced cellular proliferation, in part, through the induction of the cell cycle inhibitor, p21 WAF1/Cip1 via increased binding of Klf4 and p53 to the p21 WAF1/Cip1 promoter/enhancer. In vivo chromatin immunoprecipitation assays also showed increased Klf4 binding to the promoter/enhancer regions of the p21 WAF1/Cip1 gene and SMC differentiation marker genes following vascular injury. Taken together, we have demonstrated that Klf4 plays a critical role in regulating expression of SMC differentiation markers and proliferation of SMCs in vivo in response to vascular injury. (Circ Res. 2008;102:1548-1557.)Key Words: Krüppel-like factor Ⅲ p21 WAF1/Cip1 Ⅲ vascular injury Ⅲ conditional knockout mouse P henotypic switching of smooth muscle cells (SMCs) plays a key role in the development of vascular diseases such as atherosclerosis and restenosis after percutaneous coronary interventions. 1 Differentiated SMCs in adult vessels express a unique repertoire of contractile proteins (ie, SMC differentiation markers) and exhibit an extremely low rate of proliferation. However, in association with vascular injury or disease, SMCs modulate their phenotype and participate in the formation of neointima by markedly decreasing expression of SMC differentiation markers and increasing proliferation, migration, and synthesis of extracellular matrix proteins. Therefore, elucidation of the molecular mechanisms controlling SMC phenotypic switching is likely to provide important insights toward understanding of the development of vascular disease.A hallmark of SMC phenotypic switching is the coordinate downregulation of expression of SMC differentiation markers including smooth muscle (SM) ␣-actin, SM22␣, and SMmyosin heavy chain (SM-MHC). 1 The promoter/enhancer regions of these SMC differentiation makers contain common cis elements, including multiple CC(A/T-rich) 6 GG (CArG) elements and a transforming growth factor (TGF)-␤ control element. 1 Previously, we identified Krüppel-like factor 4 (Klf4) (formerly known as gut-enriched Krüppel-like factor or GKLF) as a binding factor for the TGF-␤ control element located within the SM22␣ promoter using a yeast 1-hybrid screen. 2 Of interest, Klf4 behaved as a potent repressor of ...

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“…Although it is generally accepted that ectopic transient VEGF expression leads to the induction of new vessels, these VEGF-induced vessels are very unstable because they lack pericytes (Sundberg et al, 2002). In order to generate a stable and functional and in particular longlasting vasculature, newly formed vessels need to be stabilised through the recruitment of mural cells, including pericytes and vascular smooth muscle cells (Lee et al, 1997;Carmeliet, 2005).…”

Section: Discussionmentioning

confidence: 99%