Integrin-Kindlin3 requirements for microglial motility in vivo are distinct from those for macrophages

Meller, Julia; Chen, Zhihong; Dudiki, Tejasvi; Cull, Rebecca M.; Murtazina, Rakhilya; Bal, Saswat Kumar; Pluskota, Elżbieta; Stefl, Samantha; Plow, Edward F.; Trapp, Bruce D.; Byzova, Tatiana V.

doi:10.1172/jci.insight.93002

Cited by 27 publications

(26 citation statements)

References 60 publications

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“…These results confirm our previous understanding that even in the absence of a stimulus, microglia are constantly surveying their microenvironment through the continuous extension and retraction of ramified projections (27,28). We did not observe any instances of microglial cell body migration, in line with a previous finding of limited movement of microglial soma (42). Conversely, we found that infiltrating BMDMs are minimally branched and highly migratory.…”

Section: Discussionsupporting

confidence: 92%

Intravital 2-photon imaging reveals distinct morphology and infiltrative properties of glioblastoma-associated macrophages

Chen

Ross

Hambardzumyan

2019

Proc. Natl. Acad. Sci. U.S.A.

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Characterized by a dismal survival rate and limited response to therapy, glioblastoma (GBM) remains one of the most aggressive human malignancies. Recent studies of the role of tumor-associated macrophages (TAMs) in the progression of GBMs have demonstrated that TAMs are significant contributors to tumor growth, invasion, and therapeutic resistance. TAMs, which include brain-resident microglia and circulating bone marrow derived-monocytes (BMDMs), are typically grouped together in histopathological and molecular analyses due to the lack of reliable markers of distinction. To develop more effective therapies aimed at specific TAM populations, we must first understand how these cells differ both morphologically and behaviorally. Furthermore, we must develop a deeper understanding of the mechanisms encouraging their infiltration and how these mechanisms can be therapeutically exploited. In this study, we combined immunocompetent lineage tracing mouse models of GBM with high-resolution open-skull 2-photon microscopy to investigate the phenotypical and functional characteristics of TAMs. We demonstrate that TAMs are composed of 2 morphologically distinct cell types that have differential migratory propensities. We show that BMDMs are smaller, minimally branched cells that are highly migratory compared with microglia, which are larger, highly branched stationary cells. In addition, 2 populations of monocytic macrophages were observed that differed in terms of CX3CR1 expression and migratory capacity. Finally, we demonstrate the efficacy of anti-vascular endothelial growth factor A blockade for prohibiting TAM infiltration, especially against BMDMs. Taken together, our data clearly define characteristics of individual TAM populations and suggest that combination therapy with antivascular and antichemotaxis therapy may be an attractive option for treating these tumors.

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Section: Discussionsupporting

confidence: 92%

Intravital 2-photon imaging reveals distinct morphology and infiltrative properties of glioblastoma-associated macrophages

Chen

Ross

Hambardzumyan

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, kindlin‐2 is the only isoform endogenously expressed in neurons and plays a role in normal axonal growth. Kindlin‐3 is predominantly expressed by cells of the immune system (Malinin et al ., ; Moser et al ., ; Feigelson et al ., ; Cohen et al ., ; Moretti et al ., ) and recently has been discovered in microglia of the brain (Meller et al ., ).…”

Section: Integrin Activators Promote Sensory Axonal Regeneration In Tmentioning

confidence: 97%

Integrins promote axonal regeneration after injury of the nervous system

et al. 2018

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Integrins are cell surface receptors that form the link between extracellular matrix molecules of the cell environment and internal cell signalling and the cytoskeleton. They are involved in several processes, e.g. adhesion and migration during development and repair. This review focuses on the role of integrins in axonal regeneration. Integrins participate in spontaneous axonal regeneration in the peripheral nervous system through binding to various ligands that either inhibit or enhance their activation and signalling. Integrin biology is more complex in the central nervous system. Integrins receptors are transported into growing axons during development, but selective polarised transport of integrins limits the regenerative response in adult neurons. Manipulation of integrins and related molecules to control their activation state and localisation within axons is a promising route towards stimulating effective regeneration in the central nervous system.

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“…K3KI knock-in mice were generated as previously described (Xu et al, 2014;Meller et al, 2017). Bones were collected from male and female K3KI mice and wild-type (WT) littermates at 9 weeks of age under a Cleveland Clinic IACUC approved animal protocol (n=14-17).…”

Section: Animal Studiesmentioning

confidence: 99%

“…The K3KI mutated Kindlin-3 knock-in mice contain a double mutation (Q 597 W 598 /AA) designed to disrupt the integrin recognition region resulting in diminished integrin binding (Xu et al, 2014(Xu et al, , 2015. Integrin expression in these mice remains equal to WT mice (Meller et al, 2017). Growth plates in 9-week old K3KI and WT mice were stained for markers of cartilage maturation.…”

Section: Mutated Kindlin-3 Mice Display Disrupted Growth Plate Chondrmentioning

confidence: 99%

Kindlin-3 Mutation in Mesenchymal Stem Cells Results in Enhanced Chondrogenesis

Kerr

Shi

Jinnah

et al. 2019

Preprint

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This study by Kerr et al. describes a new role for Kindlin-3 in controlling early chondrocyte differentiation from mesenchymal stem cells and later hypertrophic differentiation of chondrocytes. ABSTRACT Identifying patient mutations driving skeletal development disorders has driven our understanding of bone development. Integrin adhesion deficiency disease is caused by a Kindlin-3 (fermitin family member 3) mutation and its inactivation results in bleeding disorders and osteopenia. In this study, we uncover a role for Kindlin-3 in the differentiation of bone marrow mesenchymal stem cells (BMSCs) down the chondrogenic lineage. Kindlin-3 expression increased with chondrogenic differentiation similar to RUNX2. BMSCs isolated from a Kindlin-3 deficient patient expressed chondrocyte markers including SOX9 under basal conditions, which were further enhanced with chondrogenic differentiation. Rescue of integrin activation by a constitutively activated β 3 integrin construct increased adhesion to multiple extracellular matrices and reduced SOX9 expression to basal levels. Growth plates from mice expressing a mutated Kindlin-3 with the integrin binding site ablated demonstrated alterations in chondrocyte maturation similar to that seen with the human Kindlin-3 deficient BMSCs. These findings suggest that Kindlin-3 expression mirrors RUNX2 during chondrogenesis.

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Integrin-Kindlin3 requirements for microglial motility in vivo are distinct from those for macrophages

Cited by 27 publications

References 60 publications

Intravital 2-photon imaging reveals distinct morphology and infiltrative properties of glioblastoma-associated macrophages

Intravital 2-photon imaging reveals distinct morphology and infiltrative properties of glioblastoma-associated macrophages

Integrins promote axonal regeneration after injury of the nervous system

Kindlin-3 Mutation in Mesenchymal Stem Cells Results in Enhanced Chondrogenesis

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