Knockout of HIF-1  in tumor-associated macrophages enhances M2 polarization and attenuates their pro-angiogenic responses

Werno, Christian; Menrad, Heidi; Weigert, Andreas; Dehne, Nathalie; Goerdt, Sergij; Schledzewski, Kai; Kzhyshkowska, Julia; Brüne, Bernhard

doi:10.1093/carcin/bgq088

Cited by 152 publications

(143 citation statements)

References 38 publications

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“…Null mutation of Hif1a increased the expression of M2 macrophage markers and reduced expression of M1 markers, indicating that HIF1α supports the M1 phenotype (Werno et al, 2010). Interestingly, M1 macrophages might also promote vascularization through effects on stem cell differentiation, as suggested by the finding that the differentiation of embryonic stem cells into CD31 + (also known as Pecam1) endothelial cells was decreased in co-cultures with Hif1a −/− macrophages, compared with co-cultures with wild-type macrophages (Werno et al, 2010). However, this effect of M1 macrophages on adult stem cell populations has not yet been explored.…”

Section: Myeloid Cells Can Modulate Muscle Regeneration By Interactiomentioning

confidence: 97%

Shared signaling systems in myeloid cell-mediated muscle regeneration

2014

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Much of the focus in muscle regeneration has been placed on the identification and delivery of stem cells to promote regenerative capacity. As those efforts have advanced, we have learned that complex features of the microenvironment in which regeneration occurs can determine success or failure. The immune system is an important contributor to that complexity and can determine the extent to which muscle regeneration succeeds. Immune cells of the myeloid lineage play major regulatory roles in tissue regeneration through two general, inductive mechanisms: instructive mechanisms that act directly on muscle cells; and permissive mechanisms that act indirectly to influence regeneration by modulating angiogenesis and fibrosis. In this article, recent discoveries that identify inductive actions of specific populations of myeloid cells on muscle regeneration are presented, with an emphasis on how processes in muscle and myeloid cells are co-regulated. KEY WORDS: Muscle regeneration, Macrophage phenotype, Signaling systems IntroductionAcute trauma, chronic disease or disruption of vascularization cause rapid death of skeletal muscle. Functional recovery of the damaged tissue is determined by interacting cellular responses, including stem cell activation, proliferation and differentiation, vascular repair, and tissue fibrosis during healing. Experimental approaches to improve muscle regeneration have focused on identifying stem cell populations that promote regeneration and refining their delivery, while using genetic or pharmacological manipulations to influence angiogenesis and fibrosis. However, those approaches are sensitive to the presence of myeloid cells in the injured muscle, suggesting that manipulations of myeloid cells can provide novel strategies to potentiate muscle regeneration. As knowledge of myeloid cell involvement in muscle regeneration has grown, we have come to appreciate that multiple subpopulations interact in complex and delicately balanced ways to influence regeneration. Perturbations in myeloid cell number, phenotype or the stage of regeneration at which they are present can yield vastly different outcomes in the regenerative process. As these complexities become better understood, there is hope that knowledge can be exploited to improve muscle regeneration therapy.In this Review, inductive processes through which myeloid cells influence muscle regeneration are presented, including instructive processes that directly influence developmental gene expression in muscle and permissive processes that modify the environment in which regeneration occurs. Here, muscle 'regeneration' refers to processes in damaged muscle tissue that lead to the restoration of normal structure and homeostasis, especially those events that influence the differentiation and growth of muscle cells that replace damaged tissue (Box 1). In addition, we emphasize discoveries that have contributed to understanding the mechanisms that coordinate phenotypic switches in myeloid cell populations with progressive stages of musc...

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Section: Myeloid Cells Can Modulate Muscle Regeneration By Interactiomentioning

confidence: 97%

Shared signaling systems in myeloid cell-mediated muscle regeneration

2014

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“…We did not examine whether FAK deficiency of the proximal tubular epithelium alters macrophage subset polarization by induction of differential expression of proinflammatory cytokines. 34 However, because macrophage influx significantly increases at day 3 after ischemia and peaks at day 7, 35 the involvement of macrophage in the injury process studied here may be expected to be restricted to a minimum. We were able to mimic the in vivo biochemical perturbation caused by the oxidative stress associated with reperfusion after renal ischemia with the use of H 2 O 2 exposure on primary renal cells, although in vivo oxidants are usually composed of a variety of species.…”

Section: Discussionmentioning

confidence: 95%

Focal Adhesion Kinase Signaling Mediates Acute Renal Injury Induced by Ischemia/Reperfusion

Qin

Alderliesten

Stokman

et al. 2011

The American Journal of Pathology

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Renal ischemia/reperfusion (I/R) injury is associated with cell matrix and focal adhesion remodeling. Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase that localizes at focal adhesions and regulates their turnover. Here, we investigated the role of FAK in renal I/R injury, using a novel conditional proximal tubule-specific fak-deletion mouse model. Tamoxifen treatment of FAK loxP/loxP //␥GT-Cre-ER T2 mice caused renal-specific fak recombination (FAK ⌬loxP/⌬loxP ) and reduction of FAK expression in proximal tubules. In FAK ⌬loxP/⌬loxP mice compared with FAK loxP/loxP controls, unilateral renal ischemia followed by reperfusion resulted in less tubular damage with reduced tubular cell proliferation and lower expression of kidney injury molecule-1, which was independent from the postischemic inflammatory response. Oxidative stress is involved in the pathophysiology of I/R injury. Primary cultured mouse renal cells were used to study the role of FAK deficiency for oxidative stress in vitro. The conditional fak deletion did not affect cell survival after hydrogen peroxide-induced cellular stress, whereas it impaired the recovery of focal adhesions that were disrupted by hydrogen peroxide. This was associated with reduced c-Jun N-terminal kinase-dependent phosphorylation of paxillin at serine 178 in FAK-deficient cells, which is required for focal adhesion turnover. Our findings support a role for FAK as a novel factor in the initiation of c-Jun N-terminal kinase-mediated cellular stress response during renal I/R injury and suggest FAK as a target in renal injury protection.

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“…A large body of studies have highlighted that a range of HCC-derived cytokines including chemokine ligand 2 and macrophage colonystimulating factor promote recruitment of peripheral blood monocytes into tumor microenvironment and subsequently differentiation into mature macrophages which are designated as tumor-associated macrophages (TAMs) (Benetti et al, 2008;Zhu et al, 2008;Takai et al, 2009). Furthermore, activated TAMs in turn establish a distinct inflammatory microenvironment responsible for stimulating proliferation, invasion, metastasis and angiogenesis of HCC (Peng et al, 2005;Schimanski et al, 2006;Liu et al, 2008;Kuang et al, 2010;Werno et al, 2010;Chen et al, 2012). It is reasonable to believe that the vicious circle between HCC and TAMs is the driving engine of HCC for its continuous deterioration.…”

Section: Resultsmentioning

confidence: 99%