Global gene expression patterns in the post-pneumonectomy lung of adult mice

Paxson, Julia; Parkin, Christopher; Iyer, Lakshmanan K.; Mazan, Melissa R.; Ingenito, Edward P.; Hoffman, Andrew M.

doi:10.1186/1465-9921-10-92

Cited by 25 publications

(27 citation statements)

References 47 publications

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“…In the mutant mesenchyme, transgelin (Tagln)-positive smooth muscle cells were restricted to the proximal airways as in the wildtype. It has recently been shown that expression of S100 calcium binding protein A4 (S100a4) marks fibroblasts that are highly proliferative and express low levels of extracellular matrix proteins indicating the precursor character of these cells [28][29][30]. We found that in E14.5 wildtype lungs all mesenchymal cells that were positive for S100a4 also incorporated BrdU confirming the proliferative character of this cell type ( Figure S3).…”

Section: Author Summarysupporting

confidence: 65%

Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b

Lüdtke¹,

Farin²,

Rudat³

et al. 2014

Pneumologie

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Vertebrate organ development relies on the precise spatiotemporal orchestration of proliferation rates and differentiation patterns in adjacent tissue compartments. The underlying integration of patterning and cell cycle control during organogenesis is insufficiently understood. Here, we have investigated the function of the patterning T-box transcription factor gene Tbx2 in lung development. We show that lungs of Tbx2-deficient mice are markedly hypoplastic and exhibit reduced branching morphogenesis. Mesenchymal proliferation was severely decreased, while mesenchymal differentiation into fibrocytes was prematurely induced. In the epithelial compartment, proliferation was reduced and differentiation of alveolar epithelial cells type 1 was compromised. Prior to the observed cellular changes, canonical Wnt signaling was downregulated, and Cdkn1a (p21) and Cdkn1b (p27) (two members of the Cip/Kip family of cell cycle inhibitors) were strongly induced in the Tbx2-deficient lung mesenchyme. Deletion of both Cdkn1a and Cdkn1b rescued, to a large degree, the growth deficits of Tbx2-deficient lungs. Prolongation of Tbx2 expression into adulthood led to hyperproliferation and maintenance of mesenchymal progenitor cells, with branching morphogenesis remaining unaffected. Expression of Cdkn1a and Cdkn1b was ablated from the lung mesenchyme in this gain-of-function setting. We further show by ChIP experiments that Tbx2 directly binds to Cdkn1a and Cdkn1b loci in vivo, defining these two genes as direct targets of Tbx2 repressive activity in the lung mesenchyme. We conclude that Tbx2-mediated regulation of Cdkn1a and Cdkn1b represents a crucial node in the network integrating patterning information and cell cycle regulation that underlies growth, differentiation, and branching morphogenesis of this organ.

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Section: Author Summarysupporting

confidence: 65%

Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b

Lüdtke¹,

Farin²,

Rudat³

et al. 2014

Pneumologie

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“…Differentiation to lung epithelial cells was assessed by incubation of L-MSCs in small airway growth media (SAGM with SingleQuots) containing rhEGF (0.5 ng/mL) for 8 days, and measurement of Aqp5, Ttf-1, proSPC (Sftpc), and CCSP (Scgb1A1) mRNA expression. qPCR was performed according to past descriptions from our laboratory [32,37] using housekeeping genes (average of Hrtp1, GusB, and GADPH) for normalization of mRNA. Details of qPCR methodology are provided in the Supplementary Methods.…”

Section: Differentiation Assays Of L-mscsmentioning

confidence: 99%

Lung-Derived Mesenchymal Stromal Cell Post-Transplantation Survival, Persistence, Paracrine Expression, and Repair of Elastase-Injured Lung

Hoffman

Paxson

Mazan

et al. 2011

Stem Cells and Development

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While multipotent mesenchymal stromal cells have been recently isolated from adult lung (L-MSCs), there is very limited data on their biological properties and therapeutic potential in vivo. How L-MSCs compare with bone marrow-derived MSCs (BM-MSCs) is also unclear. In this study, we characterized L-MSC phenotype, clonogenicity, and differentiation potential, and compared L-MSCs to BM-MSCs in vivo survival, retention, paracrine gene expression, and repair or elastase injury after transplantation. L-MSCs were highly clonogenic, frequently expressed aldehyde dehydrogenase activity, and differentiated into osteocytes, chondrocytes, adipocytes, myofibroblasts, and smooth muscle cells. After intravenous injection (2 h), L-MSCs showed greater survival than BMMSCs; similarly, L-MSCs were significantly more resistant than BM-MSCs to anchorage independent culture (4 h) in vitro. Long after transplantation (4 or 32 days), a significantly higher number of CD45 neg L-MSCs were retained than BM-MSCs. By flow cytometry, L-MSCs expressed more intercellular adhesion molecule-1 (ICAM-1), platelet derived growth factor receptor alpha (PDGFRa), and integrin a2 than BM-MSCs; these proteins were found to modulate endothelial adherence, directional migration, and migration across Matrigel in L-MSCs. Further, L-MSCs with low ICAM-1 showed poorer lung retention and higher phagocytosis in vivo. Compared with BM-MSCs, L-MSCs expressed higher levels of several transcripts (e.g., Ccl2, Cxcl2, Cxcl10, IL-6, IL-11, Hgf, and Igf2) in vitro, although gene expression in vivo was increased by L-MSCs and BM-MSCs equivalently. Accordingly, both L-MSCs and BM-MSCs reduced elastase injury to the same extent. This study demonstrates that tissuespecific L-MSCs possess mechanisms that enhance their lung retention after intravenous transplantation, and produce substantial healing of elastase injury comparable to BM-MSCs.

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“…This is particularly applicable and appropriate to our individual time point datasets in which we have only one paired array set for each time point and has been described by our laboratory in previous analyses [19]. By definition, Sscore is related to P-value by an exponential relation, and a value of three corresponds to a P-value of 0.003 [24,27].…”

Section: Microarray Analysismentioning

confidence: 99%

“…As is seen with many mammals during periods of high somatic growth [1,17], young adult mice are capable of extensive lung regeneration after unilateral pneumonectomy [18,19]. During postpneumonectomy lung regeneration, cell proliferation occurs throughout the lung parenchyma in mesenchymal, endothelial, and epithelial compartments, as demonstrated by DNA labeling studies [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…During postpneumonectomy lung regeneration, cell proliferation occurs throughout the lung parenchyma in mesenchymal, endothelial, and epithelial compartments, as demonstrated by DNA labeling studies [19][20][21]. We have previously demonstrated that lung regeneration (compensatory lung regrowth after unilateral pneumonectomy) is age dependent in the mouse, with regenerative capacity declining as early as 9 months of age [4].…”

Section: Introductionmentioning

confidence: 99%

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Age Dependence of Lung Mesenchymal Stromal Cell Dynamics Following Pneumonectomy

Paxson

Gruntman²,

Davis³

et al. 2013

Stem Cells and Development

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Aging is a critical determinant of regenerative capacity in many organ systems, but it remains unresolved in the lung. This study examines murine lung cell dynamics during age-dependent lung regeneration. Proliferation of lung progenitor cells (EpCAM neg /Sca-1 high lung mesenchymal stromal cells -LMSCs, EpCAM pos /Sca-1 low epithelial progenitor cells, proSP-C pos alveolar type II epithelial cells -AECII, and CD31 pos -endothelial cells) was tracked to day 3 or 7 after pneumonectomy (PNX) or SHAM surgery in 3, 9, and 17 month mice. In 3 month mice, post-PNX LMSC proliferation peaked early (3 days), with 50%-80% more BrdU-positive cells than the other cell types, which peaked later (4-7 days). In older mice (9 and 17 month), abundance and post-PNX proliferation of LMSCs at day 3 were reduced (40%-80%). In both young and old mice, LMSCs were isolated and compared phenotypically with whole lung non-LMSCs. Donor age had no qualitative effect on the phenotype (LMSC vs. non-LMSC), with increased expression of CD90/Thy1, CD105/Eng, CD106/Vcam, CD146/Mcam, and Pdgfra, and up-regulation of mRNA encoding Fap, Eln, Col1a1, Col3a1, Aldh1a3, Arhgef25, Dner, Fgfr1, and Midkine. However, compared with LMSCs isolated from young mice, LMSCs from older mice exhibited reduced mRNA expression of retinoic acid (Aldh1a3, Rbp4), Fgf/Wnt (Fgfr1, Sfrp1, Wnt2, and Ctnnb1), and elastogenesis (Col1a1, Eln, Fbn1, and Sdc2) pathway genes. Isolated LMSCs from older mice also demonstrated lower colony-forming units ( -67%), growth potential ( -60% by day 7), ALDH activity ( -49%), and telomerase activity ( -47%). Therefore, age is associated with declining proliferative potential and regenerative functions of LMSCs in the lung.

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Global gene expression patterns in the post-pneumonectomy lung of adult mice

Cited by 25 publications

References 47 publications

Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b

Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b

Lung-Derived Mesenchymal Stromal Cell Post-Transplantation Survival, Persistence, Paracrine Expression, and Repair of Elastase-Injured Lung

Age Dependence of Lung Mesenchymal Stromal Cell Dynamics Following Pneumonectomy

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