High Mobility Group Box 1 (HMGB1) è una proteina nucleare ubiquitaria che viene rilasciata dalle cellule danneggiate per fornire un messaggio di danno tissutale e per attivare l'infiammazione e la rigenerazione dei tessuti. Le proprietà rigenerative di HMGB1 sono state studiate in molteplici tessuti e organi, in particolare nel muscolo scheletrico in cui HMGB1 sembra essere un fattore limitante in condizioni fisiologiche. Per identificare la fonte di HMGB1 durante la riparazione muscolare, abbiamo generato modelli murini deleti per HMGB1 specificamente in cellule miogeniche, cellule endoteliali o piastrine. Abbiamo scoperto che HMGB1 deriva principalmente da cellule non muscolari nel muscolo danneggiato. È interessante notare che ci sono stati ritardi diversi nel processo rigenerativo nei diversi topi HMGB1 specifici per le diverse cellule, questo suggerisce che HMGB1 derivato da fonti diverse svolge ruoli distinti nella rigenerazione muscolare e che è necessario un rilascio tempestivo e regolato di HMGB1 per una rigenerazione ottimale. Per sottolineare ulteriormente l'importanza di HMGB1 nel processo di rigenerazione, abbiamo generato un modello di topo deleto di HMGB1 in tutto il corpo. Come previsto, abbiamo osservato una grave compromissione della rigenerazione muscolare e, più specificamente, un ritardo nel reclutamento dei leucociti, confermando il ruolo cruciale di HMGB1 in questo processo. A parte rari studi incentrati principalmente sui macrofagi, il destino di HMGB1 dopo il rilascio nell'ambiente extracellulare rimane in gran parte inesplorato. Questa è una domanda chiave perché un’accurata regolazione del livello extracellulare di HMGB1 è essenziale per supportare la rigenerazione dei tessuti ma anche per evitare effetti dannosi come l'infiammazione persistente. Abbiamo scoperto l'interiorizzazione di HMGB1, come meccanismo di riciclo durante la rigenerazione del muscolo scheletrico, che sembra essere importante per il controllo delle dimensioni delle miofibre. Allo stesso modo, abbiamo osservato il riciclo di HMGB1 nel microambiente tumorale e i dati preliminari indicano che questo processo potrebbe contribuire alla riparazione del DNA in risposta alla radioterapia. Abbiamo identificato gli eparan solfati come mediatori dell'internalizzazione di HMGB1 e più specificamente syndecan-4. In conclusione, i nostri risultati sottolineano ulteriormente l'importanza di HMGB1 nel processo di rigenerazione e hanno svelato la sua internalizzazione come meccanismo di riciclo nel muscolo danneggiato e nel microambiente tumorale. Questo processo di risparmio proteico potrebbe svolgere un ruolo fondamentale nella rigenerazione dei tessuti così come nella progressione del cancro e, più in generale, in molte condizioni fisiologiche e patologiche in cui è stato riportato il contributo di HMGB1.

High Mobility Group Box 1 (HMGB1) is a ubiquitous nuclear protein that is released by injured cells to serve a soluble message of tissue damage and to trigger inflammation and tissue regeneration. The regenerative properties of HMGB1 have been investigated in multiple tissues and organs, especially in skeletal muscle in which HMGB1 appears to be a limiting factor in physiological conditions. To identify the source(s) of HMGB1 during muscle repair, we generated conditional HMGB1 knockout mouse models with specific deletion in myogenic cells, endothelial cells or platelets. We found that HMGB1 mainly derives from non-muscle cells in injured muscle. Interestingly, there were distinct delays in the regenerative process in the different cell-specific HMGB1 KO mice, indicating that HMGB1 derived from different sources plays distinct roles in muscle regeneration and that a timely and spatially regulated release of HMGB1 is required for optimal regeneration. To further emphasize the importance of HMGB1 in the regeneration process, we generated a whole body inducible HMGB1 KO mouse model. As expected, we observed a severe impairment in muscle regeneration, and more specifically a delay in leucocyte recruitment, confirming the crucial role of HMGB1 in this process. Apart from rare studies mainly focused on macrophages, the fate of HMGB1 after release in the extracellular environment remains largely unexplored. This is a key question because a tight regulation of HMGB1 extracellular level is essential to support tissue regeneration but also to avoid detrimental effects such as persistent inflammation. We uncovered HMGB1 internalization, as a mechanism of recycling during skeletal muscle regeneration, that appears to be important for the control of myofiber size. Similarly, we observed HMGB1 recycling in the tumor microenvironment and preliminary data indicate that this process might contribute to DNA repair in response to radiotherapy. We identified heparan sulfate proteoglycans as mediators of HMGB1 internalization, and more specifically syndecan-4. In conclusion, our findings further emphasize the importance of HMGB1 in the regeneration process and unraveled its internalization as a mechanism of recycling in injured muscle and tumor microenvironment. This protein-saving process might play pivotal roles in tissue regeneration as well as in cancer progression and, more generally, in many physiological and pathological conditions in which the contribution of HMGB1 has been reported.

Discovery of HMGB1 recycling as a novel rheostat in muscle regeneration and tumor microenvironment / Elena Ruggieri - : . , 2022 May 13. ((34. ciclo, Anno Accademico 2020/2021.

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Discovery of HMGB1 recycling as a novel rheostat in muscle regeneration and tumor microenvironment

RUGGIERI, ELENA
2022

Abstract

High Mobility Group Box 1 (HMGB1) is a ubiquitous nuclear protein that is released by injured cells to serve a soluble message of tissue damage and to trigger inflammation and tissue regeneration. The regenerative properties of HMGB1 have been investigated in multiple tissues and organs, especially in skeletal muscle in which HMGB1 appears to be a limiting factor in physiological conditions. To identify the source(s) of HMGB1 during muscle repair, we generated conditional HMGB1 knockout mouse models with specific deletion in myogenic cells, endothelial cells or platelets. We found that HMGB1 mainly derives from non-muscle cells in injured muscle. Interestingly, there were distinct delays in the regenerative process in the different cell-specific HMGB1 KO mice, indicating that HMGB1 derived from different sources plays distinct roles in muscle regeneration and that a timely and spatially regulated release of HMGB1 is required for optimal regeneration. To further emphasize the importance of HMGB1 in the regeneration process, we generated a whole body inducible HMGB1 KO mouse model. As expected, we observed a severe impairment in muscle regeneration, and more specifically a delay in leucocyte recruitment, confirming the crucial role of HMGB1 in this process. Apart from rare studies mainly focused on macrophages, the fate of HMGB1 after release in the extracellular environment remains largely unexplored. This is a key question because a tight regulation of HMGB1 extracellular level is essential to support tissue regeneration but also to avoid detrimental effects such as persistent inflammation. We uncovered HMGB1 internalization, as a mechanism of recycling during skeletal muscle regeneration, that appears to be important for the control of myofiber size. Similarly, we observed HMGB1 recycling in the tumor microenvironment and preliminary data indicate that this process might contribute to DNA repair in response to radiotherapy. We identified heparan sulfate proteoglycans as mediators of HMGB1 internalization, and more specifically syndecan-4. In conclusion, our findings further emphasize the importance of HMGB1 in the regeneration process and unraveled its internalization as a mechanism of recycling in injured muscle and tumor microenvironment. This protein-saving process might play pivotal roles in tissue regeneration as well as in cancer progression and, more generally, in many physiological and pathological conditions in which the contribution of HMGB1 has been reported.
Discovery of HMGB1 recycling as a novel rheostat in muscle regeneration and tumor microenvironment / Elena Ruggieri - : . , 2022 May 13. ((34. ciclo, Anno Accademico 2020/2021.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/130173
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