Resistin-Like Molecule α Stimulates Proliferation of Mesenchymal Stem Cells While Maintaining Their Multipotency

Kolosova, Irina; Angelini, Daniel J.; Fan, Chunling; Skinner, John; Cheadle, Christopher; Johns, Roger A.

doi:10.1089/scd.2012.0192

Cited by 15 publications

(17 citation statements)

References 38 publications

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“…This is also consistent with our observations that HIMF is upregulated in the vascular smooth muscle cells that are undergoing cell division [proliferating cell nuclear antigen (PCNA)- and/or Ki67-positive]. Other work from our laboratory supports this hyperplastic role for HIMF, as we have found HIMF to exert a marked shift in human mesenchymal cells to a dividing phenotype [64]. Because HIMF is primarily expressed during the early hyperplastic phase of chronic hypoxia and we have demonstrated that preventing such expression prevents long-term remodeling associated with chronic hypoxia [20], we hypothesize that HIMF acts as an initiating factor for pulmonary vascular remodeling.…”

Section: Discussionsupporting

confidence: 92%

Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in chronic hypoxia- and antigen-mediated pulmonary vascular remodeling

Angelini

Yamaji-Kegan

et al. 2013

Respir Res

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BackgroundBoth chronic hypoxia and allergic inflammation induce vascular remodeling in the lung, but only chronic hypoxia appears to cause PH. We investigate the nature of the vascular remodeling and the expression and role of hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in explaining this differential response.MethodsWe induced pulmonary vascular remodeling through either chronic hypoxia or antigen sensitization and challenge. Mice were evaluated for markers of PH and pulmonary vascular remodeling throughout the lung vascular bed as well as HIMF expression and genomic analysis of whole lung.ResultsChronic hypoxia increased both mean pulmonary artery pressure (mPAP) and right ventricular (RV) hypertrophy; these changes were associated with increased muscularization and thickening of small pulmonary vessels throughout the lung vascular bed. Allergic inflammation, by contrast, had minimal effect on mPAP and produced no RV hypertrophy. Only peribronchial vessels were significantly thickened, and vessels within the lung periphery did not become muscularized. Genomic analysis revealed that HIMF was the most consistently upregulated gene in the lungs following both chronic hypoxia and antigen challenge. HIMF was upregulated in the airway epithelial and inflammatory cells in both models, but only chronic hypoxia induced HIMF upregulation in vascular tissue.ConclusionsThe results show that pulmonary vascular remodeling in mice induced by chronic hypoxia or antigen challenge is associated with marked increases in HIMF expression. The lack of HIMF expression in the vasculature of the lung and no vascular remodeling in the peripheral resistance vessels of the lung is likely to account for the failure to develop PH in the allergic inflammation model.

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Section: Discussionsupporting

confidence: 92%

Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in chronic hypoxia- and antigen-mediated pulmonary vascular remodeling

Angelini

Yamaji-Kegan

et al. 2013

Respir Res

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“…Although here we found that HIMF caused EC apoptosis, we have reported previously that HIMF promotes proliferation of specific cell types by mediating the cell survival proteins Akt and ERK (27). Indeed, we have shown that low concentrations of HIMF (Ͻ10 nM) have proliferative effects on ECs (60), suggesting that HIMF has dual and separate actions depending on its concentration.…”

Section: Discussionmentioning

confidence: 45%

“…EC exocytosis components are known to mobilize stem and progenitor cells for the regeneration of an injured organ (31). Indeed, we have shown previously that HIMF causes strong proliferative activity in human mesenchymal stem cells (27), suggesting that it has separate and distinct effects on precursor cells and lung resident endothelium in response to injury. hRETN has been shown to activate ECs in cardiovascular diseases (17,58); however, this is the first report to show its effect on apoptosis, Ang2 induction, and EC-mediated SMC proliferation.…”

Section: Discussionmentioning

confidence: 90%

Hypoxia-induced mitogenic factor (FIZZ1/RELMα) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension

Yamaji-Kegan

Takimoto

Zhang

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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RA. Hypoxia-induced mitogenic factor (FIZZ1/RELM␣) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension. Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right heart failure and ultimately death. Injury to endothelium and consequent wound repair cascades have been suggested to trigger pulmonary vascular remodeling, such as that observed during PH. The relationship between injury to endothelium and disease pathogenesis in this disorder remains poorly understood. We and others have shown that, in mice, hypoxia-induced mitogenic factor (HIMF, also known as FIZZ1 or RELM␣) plays a critical role in the pathogenesis of lung inflammation and the development of PH. In this study, we dissected the mechanism by which HIMF and its human homolog resistin (hRETN) induce pulmonary endothelial cell (EC) apoptosis and subsequent lung inflammation-mediated PH, which exhibits many of the hallmarks of the human disease. Systemic administration of HIMF caused increases in EC apoptosis and interleukin (IL)-4-dependent vascular inflammatory marker expression in mouse lung during the early inflammation phase. In vitro, HIMF, hRETN, and IL-4 activated pulmonary microvascular ECs (PMVECs) by increasing angiopoietin-2 expression and induced PMVEC apoptosis. In addition, the conditioned medium from hRETN-treated ECs had elevated levels of endothelin-1 and caused significant increases in pulmonary vascular smooth muscle cell proliferation. Last, HIMF treatment caused development of PH that was characterized by pulmonary vascular remodeling and right heart failure in wild-type mice but not in IL-4 knockout mice. These data suggest that HIMF contributes to activation of vascular inflammation at least in part by inducing EC apoptosis in the lung. These events lead to subsequent PH. endothelial apoptosis; T-helper type 2 inflammation; human resistin PULMONARY HYPERTENSION (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right-sided heart failure. It is associated with significant morbidity and mortality. Despite major advances in diagnosis and treatment of this disease over the last several decades, the underlying mechanisms of PH remain enigmatic. In humans, severe pulmonary arterial hypertension (PAH, idiopathic PH) is characterized by plexiform lesions that contain phenotypically altered pulmonary smooth muscle and endothelial cells (ECs) (56). Evidence suggests that early EC apoptosis may trigger both degenerative and reactive proliferative events that result in the pulmonary vascular pathology of PH (25). Failure to stop the initial repair response could result in pathophysiological vascular remodeling, such as that which occurs during PH (25). Strong circumstantial clinical evidence supports an immune pathogenesis of PH, but whether the immunological features are a cause or consequence of PH is unknown. It has been shown that vascular endothelial growth factor (VEGF) receptor (VEGFR) blockade with Su...

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“…The resistin like alpha ( Retnla/RELMα/Fizz1 ) gene was one of the two targets identified in both T0 and T2 mice. Expression of RELMα is usually low in normal mouse lung, but it is greatly increased during hypoxia‐induced pulmonary hypertension, allergic airway inflammation, bleomycin‐induced lung fibrosis, and asthma . Kolosova et al .…”

Section: Discussionmentioning

confidence: 99%

“…Kolosova et al . showed that RELMa induces robust proliferation of mesenchymal stem cells (MSC) in mouse lung dependent on Pi3k/Akt and Erk activation . The gamma‐glutamyltransferase 1 ( Ggt1 ) gene was another common target in T0 and T2 mice.…”

Section: Discussionmentioning

confidence: 99%

Exposure of mice to secondhand smoke elicits both transient and long‐lasting transcriptional changes in cancer‐related functional networks

Tommasi

Zheng

Besaratinia

2014

Intl Journal of Cancer

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Secondhand smoke (SHS) has long been linked to lung cancer and other diseases in nonsmokers. Yet, the underlying mechanisms of SHS carcinogenicity in nonsmokers remain to be elucidated. We investigated the immediate and long-lasting effects of SHS exposure on gene expression in mice in vivo. We exposed mice whole body to SHS for 5 h/day, 5 days/week for 4 months in exposure chambers of a microprocessor-controlled smoking machine. Subsequently, we performed microarray gene expression profiling, genome-wide, to construct the pulmonary transcriptome of SHS-exposed mice, immediately after discontinuation of exposure (T0) and following 1-month (T1) and 7-month (T2) recoveries in clean air. Sub-chronic exposure of mice to SHS elicited a robust transcriptomic response, including both reversible and irreversible changes in gene expression. There were 674 differentially expressed transcripts immediately after treatment (T0), of which the majority were involved in xenobiotic metabolism, signaling, and innate immune response. Reduced, yet, substantial numbers of differentially expressed transcripts were detectable in mice after cessation of SHS-exposure (254 transcripts at T1 and 30 transcripts at T2). Top biofunctional networks disrupted in SHS-exposed mice, even after termination of exposure, were implicated in cancer, respiratory disease, and inflammatory disease. Our data show that exposure of mice to SHS induces both transient and long-lasting changes in gene expression, which impact cancer-related functional networks. The pattern of transcriptional changes in SHSexposed mice may provide clues on the underlying mechanisms of lung tumorigenesis in nonsmokers. Our findings underscore the importance of eliminating SHS from environments where nonsmokers are unavoidably exposed to this carcinogen.

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Resistin-Like Molecule α Stimulates Proliferation of Mesenchymal Stem Cells While Maintaining Their Multipotency

Cited by 15 publications

References 38 publications

Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in chronic hypoxia- and antigen-mediated pulmonary vascular remodeling

Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in chronic hypoxia- and antigen-mediated pulmonary vascular remodeling

Hypoxia-induced mitogenic factor (FIZZ1/RELMα) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension

Exposure of mice to secondhand smoke elicits both transient and long‐lasting transcriptional changes in cancer‐related functional networks

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