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Molon, Sibilla (2016) Role of collagen VI in skeletal muscle regeneration and intestinal homeostasis. [Tesi di dottorato]

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Abstract (inglese)

During my PhD I focused on the role of collagen VI in skeletal muscle regeneration and in intestinal homeostasis. Collagen VI is a glycoprotein of the extracellular matrix (ECM) containing three genetically distinct chains and forming an extended microfilamentous network that interacts with the cells and with other ECM components. Mutations of collagen VI genes in humans cause several muscle diseases, including Bethlem myopathy and Ullrich congenital muscle dystrophy. The generation of a collagen VI knockout mouse model was fundamental for clarifying the pathomolecular defects caused by the absence of this protein and provided a valuable tool for developing novel therapeutic opportunities in patients. During the past decade, studies on collagen VI null mice revealed an increasingly important role for this ECM component in a plethora of different cell and tissue processes, including apoptosis and oxidative damage, autophagy, cell differentiation, maintenance of stemness, regulation of tissue regeneration and biomechanical properties.
In the first part of my PhD work, I was involved in a large project aimed at characterizing the role of collagen VI in muscle regeneration and in the regulation of the activities of satellite cells (SCs), the main adult stem cell population of skeletal muscles. Our studies revealed that collagen VI is a key component of the SC niche, and its lack affects muscle regeneration and impairs SC self-renewal in collagen VI null mice. Interestingly, we found that the absence of collagen VI affects the in vivo mechanical properties of skeletal muscles. Furthermore, in vitro studies revealed that SC stemness and regenerative capabilities are strongly compromised when SCs are cultured on biomimetic substrates with the abnormal stiffness displayed by collagen VI deficient muscles, compared to SCs cultured on biomimetic substrates with the normal muscle stiffness. Both the biomechanical properties value and the regenerative capability of collagen VI null muscle are improved after in vivo grafting with wild-type muscle fibroblasts, the main cell type producing collagen VI, thus pointing out that a key mechanism by which collagen VI regulates SC activity is via modulation of muscle mechanical properties. In a subsequent work, we found that pharmacological treatment of collagen VI null mice with cyclosporin A is able to stimulate myogenesis in physiological conditions by increasing the percentage of regenerating myofibers, and to improve muscle regeneration and SC homeostasis after cardiotoxin-induced injury.
In the second part of my PhD, I investigated the role of collagen VI in intestine. Despite its broad distribution within the mucosa and the smooth muscle layers of the digestive tract, lack of collagen VI does not trigger any gross abnormality in the intestinal architecture of knockout mice. However, studies of the gastrointestinal functionality revealed that the lack of this ECM component lead to increased motility and decreased paracellular permeability. Induction of experimental acute colitis by administration of dextran sodium sulphate showed that collagen VI deficient mice have a decreased responsiveness and severity to acute colitis, with a lower body weight loss and decreased colonic inflammation when compared to wild-type subjected to the same treatment. Moreover, wild-type mice displayed an increased recruitment of inflammatory cells, in association with increased macrophage number and neutrophil activity, which decreased during 10 days of recovery subsequent to acute colitis, thus allowing proper tissue repair. Conversely, collagen VI deficient mice were unable to efficiently turn off inflammation during post-colitis recovery, displaying a high number of pro-inflammatory M1 colonic macrophages, an increased neutrophil activity and a higher body weight loss when compared to wild-type. Moreover, lack of collagen VI affected both macrophage polarization and activity in physiological conditions and during mild inflammation. Further studies allowed to reveal that lack of collagen VI affects the behavior of intestinal macrophages, both in physiological conditions and during mild inflammation, whose activity is essential to ensure intestinal mucosa homeostasis. These findings point at a role for collagen VI as a chemoattractant during acute inflammation and in tissue regeneration in the subsequent recovery phase. Immunofluorescence studies revealed an increased deposition of collagen VI in the colonic mucosa during acute colitis, and the protein was found in contact with macrophages. Interestingly, ileal biopsies of Crohn’s disease patients displayed increased expression and deposition of collagen VI, in association with a high number of macrophages, suggesting that the dysregulation of this ECM component may play an active role in the onset and/or maintenance of inflammatory bowel diseases.
In conclusion, my PhD work provided novel information on the in vivo roles of collagen VI in cell and tissue homeostasis. In more general terms, these findings highlight the importance of a specific defined ECM microenvironment to ensure tissue homeostasis, and demonstrate that lack of one of the major ECM component may have a severe impact on cell behavior.

Abstract (italiano)

Durante il mio percorso di dottorato mi sono occupata di studiare il ruolo del collagene VI nella rigenerazione del muscolo scheletrico e nell’omeostasi dell’intestino. Il collagene VI è una glicoproteina della matrice extracellulare (MEC) costituita da tre catene geneticamente distinte, le quali si organizzano in modo da formare un’estesa rete di microfilamenti in grado di connettere cellule e altri componenti della MEC. Mutazioni a carico dei geni codificanti le catene del collagene VI causano diverse patologie muscolari, principalmente la miopatia di Bethlem e la distrofia muscolare congenita di Ullrich. Gli studi condotti sul modello knockout murino privo di collagene VI hanno permesso di chiarire i difetti patomolecolari causati dall’assenza di questa proteina, dimostrandosi utile anche per l’identificazione di nuovi trattamenti farmacologici per le malattie umane. Nel coso degli anni, molteplici studi hanno messo in luce le diverse funzioni esercitate dal collagene VI nel regolare diversi eventi cellulari e tissutali, tra cui l’apoptosi e il danno ossidativo, l’autofagia, il differenziamento cellulare, il mantenimento della staminalità ai fini rigenerativi e le proprietà biomeccaniche.
Nel corso del mio dottorato ho partecipato inizialmente alla caratterizzazione del ruolo del collagene VI durante la rigenerazione del muscolo scheletrico e la sua influenza sull’attività delle cellule satelliti, la popolazione principale di cellule staminali adulte nei muscoli scheletrici. Da tali studi è emerso che il collagene VI è un componente essenziale della nicchia delle cellule satelliti. La mancanza di tale proteina determina una ridotta rigenerazione tissutale e una diminuita capacità delle cellule satelliti di compiere self-renewal in seguito a danni muscolari multipli. I muscoli dei topi privi di collagene VI sono caratterizzati da una minore stiffness e approfondite analisi condotte in vitro hanno rivelato che le proprietà staminali e rigenerative delle cellule satelliti sono fortemente compromesse quando coltivate su biomateriali con un modulo elastico che mima la condizione patologica. Le capacità rigenerative e le proprietà meccaniche dei muscoli di topi privi di collagen VI vengono ripristinate in seguito alla deposizione di collagene VI, ristabilita tramite grafting di fibroblasti muscolari isolati da topi wild-type. Complessivamente, questi studi hanno dimostrato che modulando le proprietà meccaniche del muscolo, il collagene VI è in grado di regolare l’attività delle cellule satelliti. Abbiamo inoltre dimostrato che la somministrazione di ciclosporina A è in grado di stimolare la miogenesi in condizioni fisiologiche, inducendo la formazione di nuove fibre muscolari, e di migliorare la rigenerazione muscolare e l’omeostasi delle cellule satelliti in seguito a danni muscolari nei topi privi di collagene VI.
Successivamente mi sono dedicata ad indagare il ruolo del collagene VI nell’omeostasi dell’intestino. Sebbene questa proteina sia ampiamente distribuita nella mucosa e nello strato muscolare, la sua assenza sembra non comportare alterazioni macroscopiche sull’architettura intestinale. L’analisi della funzionalità del sistema gastrointestinale ha evidenziato un’aumentata motilità e una ridotta permeabilità paracellulare in assenza di collagene VI. Esperimenti di induzione di colite acuta mediante sodio solfato destano hanno rivelato che i topi privi di collagene VI presentano una ridotta risposta e severità, associate ad una minore perdita di peso corporeo e minore infiammazione della mucosa del colon rispetto ai topi wild-type. Inoltre, durante la fase di colite acuta il reclutamento di cellule infiammatorie è risultato essere aumentato nei topi wild-type, comportando un aumento del numero di macrofagi e di attività dei neutrofili, mentre si riduce durante la fase di recupero seguente la colite acuta, favorendo la rigenerazione tissutale. Di contro, nei topi privi di collagene VI l’infiammazione è risultata essere ancora attiva durante la fase di recupero, con un elevato numero di macrofagi pro-infiammatori M1, un’alta attività dei neutrofili e un peggioramento della perdita di peso. Inoltre l’assenza di collagene VI ha dimostrato influenzare il comportamento dei macrofagi della mucosa del colon, sia in condizioni fisiologiche sia durante i primi giorni di infiammazione acuta, la cui attività è essenziale per assicurare l’omeostasi della mucosa intestinale. Nel complesso, da questi studi è emerso che il collagene VI esercita un ruolo da chemoattrattore per le cellule infiammatorie durante la fase di colite acuta, mentre nella successiva fase di risoluzione la sua presenza è necessaria nell’indurre una corretta rigenerazione tissutale. Studi di immunofluorescenza hanno inoltre rivelato nei topi wild-type un’elevata espressione di collagene VI in stretto contatto con i macrofagi della mucosa del colon durante la fase di colite acuta. L’evidenza di un’aumentata espressione di collagene VI su biopsia di ileo di paziente affetto da morbo di Crohn, associata ad un elevato numero di macrofagi rispetto al controllo sano, suggerisce un coinvolgimento di questo componente della MEC nel decorso delle malattie infiammatorie intestinali.
In conclusione, le evidenze emerse in questo mio lavoro di tesi avvalorano l’importanza del ruolo della matrice extracellulare nell’omeostasi tissutale.

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Tipo di EPrint:Tesi di dottorato
Relatore:Dalla Valle, Luisa
Correlatore:Bonaldo, Paolo
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > BIOMEDICINA > MEDICINA RIGENERATIVA
Data di deposito della tesi:29 Gennaio 2016
Anno di Pubblicazione:29 Gennaio 2016
Parole chiave (italiano / inglese):extracellular matrix, collagen VI, satellite cells, skeletal muscle regeneration, intestine, colitis, intestinal macrophages
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:9380
Depositato il:20 Ott 2016 10:19
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