Adrenomedullin Regenerates Alveoli and Vasculature in Elastase-induced Pulmonary Emphysema in Mice

Murakami, Shigetaka; Nagaya, Noritoshi; Itoh, Takefumi; Igarashi, Takashi; Fujisato, Toshiya; Nishioka, Keisuke; Hamada, Kaoru; Kangawa, Kenji; Kimura, Hiroshi

doi:10.1164/rccm.200409-1280oc

Cited by 72 publications

(46 citation statements)

References 43 publications

(50 reference statements)

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“…Data for engraftment of marrow-derived cells as lung epithelial cells have been reported by our group as well as others (6)(7)(8)(9)(10)(11)(12)(13)(14), and some forms of lung injury promote mobilization of hematopoietic stem and progenitor cells from the BM into the circulation (14,15). There exists some controversy in this area, because a number of investigators using alternate approaches have found no evidence of BM contribution to epithelial repair in the murine lung (16)(17)(18).…”

Section: Bm Cells Can Develop Into Epithelial Cells In Micementioning

confidence: 76%

Engraftment of Marrow-derived Epithelial Cells: The Role of Fusion

Herzog¹,

Krause²

2006

Proceedings of the American Thoracic Society

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Contribution of transplanted bone marrow has, in many models, led to the appearance of marrow-derived epithelial cells in a variety of organs, including the lung. Following the initial descriptions of these cells, many questions remain about the mechanisms by which bone marrow adopts an epithelial phenotype in the murine lung. Data from other epithelial lineages, such as those of the kidney and colon, suggest that one mechanism is fusion of transplanted marrow with host pneumocytes. This process appears to require severe damage and may not be the only mechanism by which mature lung epithelia can derive from marrow. This article discusses the processes leading to the appearance of marrow-derived pneumocytes and highlights the therapeutic potential of bone marrow to fuse with or differentiate into epithelial cells of the lung. Keywords: Bone marrow; stem cell plasticityWe and others have demonstrated that bone marrow-derived cells (BMDCs) can develop into epithelial cells in the lung, liver, gastrointestinal (GI) tract, and skin. These findings, initially reported in laboratory animals, have also been reported in humans. It is not yet clear which subpopulation(s) of the bone marrow (BM) has the ability to become epithelial cells. Another unresolved question regarding this BM to epithelial transition is the mechanism by which this occurs. Data suggest that cell-cell fusion can occur but is not required. We hypothesize that both the degree of epithelial engraftment and the mechanism by which this occurs in the lung are dependent on the degree and type of damage induced. Here, we review the data regarding the mechanisms underlying the BM to epithelial transition with an emphasis on the role of cell fusion. In addition, we present data regarding the feasibility of using BM cells as a vehicle to deliver gene therapy to the lung. BM CELLS CAN DEVELOP INTO EPITHELIAL CELLS IN MICEIn the earliest studies demonstrating marrow-derived epithelial cells, Petersen and colleagues (1) and Theise and coworkers (2) showed that female rats and mice that had been lethally irradiated and transplanted with male BM developed Y chromosomepositive hepatocytes. These data were obtained by other laboratories as well, and the reported level of engraftment varied widely, from 0.01 to 2%. This is likely due to multiple variables, including the degree and type of injury induced in the liver, the cell population transplanted, and the method of detection used. BMDCs have also been reported to take on the gene expression

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Section: Bm Cells Can Develop Into Epithelial Cells In Micementioning

confidence: 76%

Engraftment of Marrow-derived Epithelial Cells: The Role of Fusion

Herzog¹,

Krause²

2006

Proceedings of the American Thoracic Society

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“…Adm is an hypoxia-inducible peptide with vasodilative, antioxidative, and angiogenic properties and is highly expressed in the developing lung. Not only has Adm been reported to regulate cell growth and survival, to induce proliferation and migration of endothelial progenitor cells, to enhance the regenerating potential of the latter for pulmonary endothelium (36), and to regenerate alveoli and vasculature in elastase-induced pulmonary emphysema (35), but its role in alveolar development was recently shown (46). Lung expression of its transcript increases during alveolar development in rat lung also, and a requirement for Adm for alveolar septation and angiogenesis was demonstrated in this species (46).…”

Section: Discussionmentioning

confidence: 99%

Profiling target genes of FGF18 in the postnatal mouse lung: possible relevance for alveolar development

Franco-Montoya

Boucherat

Thibault

et al. 2011

Physiological Genomics

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Better understanding alveolarization mechanisms could help improve prevention and treatment of diseases characterized by reduced alveolar number. Although signaling through fibroblast growth factor (FGF) receptors is essential for alveolarization, involved ligands are unidentified. FGF18, the expression of which peaks coincidentally with alveolar septation, is likely to be involved. Herein, a mouse model with inducible, lung-targeted FGF18 transgene was used to advance the onset of FGF18 expression peak, and genome-wide expression changes were determined by comparison with littermate controls. Quantitative RT-PCR was used to confirm expression changes of selected up- and downregulated genes and to determine their expression profiles in the course of lung postnatal development. This allowed identifying so-far unknown target genes of the factor, among which a number are known to be involved in alveolarization. The major target was adrenomedullin, a promoter of lung angiogenesis and alveolar development, whose transcript was increased 6.9-fold. Other genes involved in angiogenesis presented marked expression increases, including Wnt2 and cullin2. Although it appeared to favor cell migration notably through enhanced expression of Snai1/2, FGF18 also induced various changes consistent with prevention of epithelial-mesenchymal transition. Together with antifibrotic effects driven by induction of E prostanoid receptor 2 and repression of numerous myofibroblast markers, this could prevent alveolar septation-driving mechanisms from becoming excessive and deleterious. Last, FGF18 up- or downregulated genes of extracellular matrix components and epithelial cell markers previously shown to be up- or downregulated during alveolarization. These findings therefore argue for an involvement of FGF18 in the control of various developmental events during the alveolar stage.

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“…47 Treatment with adrenomedullin was associated with increased numbers of mononuclear cells and sca-1 positive cells in circulating blood, and increased numbers of bone marrow derived cells within the elastasetreated lung. The authors concluded that adrenomedullin may improve emphysema by mobilizing bone marrow cells and protecting alveolar epithelia and endothelial cells against tissue destruction.…”

Section: Potential Mechanisms To Enhance Resident Stem Cell Regenerationmentioning

confidence: 92%

Potential role of stem cells in management of COPD

Hackett

Knight²,

Sin

2010

COPD

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Chronic obstructive pulmonary disease (COPD) is a worldwide epidemic affecting over 200 million people and accounting for more than three million deaths annually. The disease is characterized by chronic inflammation of the airways and progressive destruction of lung parenchyma, a process that in most cases is initiated by cigarette smoking. Unfortunately, there are no interventions that have been unequivocally shown to prolong survival in patients with COPD. Regeneration of lung tissue by stem cells from endogenous and exogenous sources is a promising therapeutic strategy. Herein we review the current literature on the characterization of resident stem and progenitor cell niches within the lung, the contribution of mesenchymal stem cells to lung regeneration, and advances in bioengineering of lung tissue.

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Adrenomedullin Regenerates Alveoli and Vasculature in Elastase-induced Pulmonary Emphysema in Mice

Abstract: Adrenomedullin improved elastase-induced emphysema at least in part through mobilization of bone marrow cells and the direct protective effects on alveolar epithelial cells and endothelial cells.

Cited by 72 publications

References 43 publications

Engraftment of Marrow-derived Epithelial Cells: The Role of Fusion

Engraftment of Marrow-derived Epithelial Cells: The Role of Fusion

Profiling target genes of FGF18 in the postnatal mouse lung: possible relevance for alveolar development

Potential role of stem cells in management of COPD

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