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p16INK4A-expressing mesenchymal stromal cells restore the senescence-clearance-regeneration sequence that is impaired in chronic muscle inflammation

Chikenji, TS;Saito, Y;Konari, N;Nakano, M;Mizue, Y;Otani, M;Fujimiya, M;
Product: Pertussis Toxin from B. pertussis, Lyophilized in Buffer

The therapeutic benefits of mesenchymal stromal cells (MSCs) include treatment of chronic inflammation. However, given the short-lived engraftment of these cells in vivo, their therapeutic efficacy remains mysterious. Transient induction of cellular senescence contributes to activation of immune cells, which promotes clearance of damaged cells during tissue remodelling. This may occur in tissue-resident mesenchymal progenitor cells during regeneration. Elucidation of the role of senescence in tissue-resident mesenchymal progenitor cells during regeneration would provide insight into the profile of therapeutic MSCs for treatment of chronic inflammatory disease. We evaluated multipotent mesenchymal progenitor cells, termed fibro/adipogenic progenitors (FAPs), and immune cells in acute muscle injury (AMI) model mice and mice with myosin-induced experimental autoimmune myositis, a model of chronic inflammatory myopathy (CIM). Human bone marrow MSCs were optimised for the treatment of CIM using placental extract. FAPs in AMI transiently expressed p16INK4A on days 1 and 2 after injury and recruited phagocytic immune cells, whereas in CIM, p16INK4A expression in FAPs was low. Cellular senescence occurs during the natural maturation of the placenta. Therefore, we used human placental extract to induce p16INK4A expression in therapeutic human bone marrow MSCs in culture. Treatment of CIM with p16INK4A-expressing MSCs promoted tissue remodelling by transiently increasing the abundance of engrafted MSCs, inducing cellular senescence in innate FAPs, and recruiting phagocytic immune cells. MSCs may exert their effect by remodelling the chronic inflammatory environment via senescence-related regenerative processes. Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

PubMed ID: 31129096
359435942019-06-172019-06-1714:32:1914:32:192019-07-052019-07-0515:20:5715:20:57Chikenji, TS;Saito, Y;Konari, N;Nakano, M;Mizue, Y;Otani, M;Fujimiya, M;Chikenji, TS;Saito, Y;Konari, N;Nakano, M;Mizue, Y;Otani, M;Fujimiya, M;20192019p16INK4A-expressing mesenchymal stromal cells restore the senescence-clearance-regeneration sequence that is impaired in chronic muscle inflammationp16INK4A-expressing mesenchymal stromal cells restore the senescence-clearance-regeneration sequence that is impaired in chronic muscle inflammationEbiomedicineEbiomedicine3112909631129096

The therapeutic benefits of mesenchymal stromal cells (MSCs) include treatment of chronic inflammation. However, given the short-lived engraftment of these cells in vivo, their therapeutic efficacy remains mysterious. Transient induction of cellular senescence contributes to activation of immune cells, which promotes clearance of damaged cells during tissue remodelling. This may occur in tissue-resident mesenchymal progenitor cells during regeneration. Elucidation of the role of senescence in tissue-resident mesenchymal progenitor cells during regeneration would provide insight into the profile of therapeutic MSCs for treatment of chronic inflammatory disease. We evaluated multipotent mesenchymal progenitor cells, termed fibro/adipogenic progenitors (FAPs), and immune cells in acute muscle injury (AMI) model mice and mice with myosin-induced experimental autoimmune myositis, a model of chronic inflammatory myopathy (CIM). Human bone marrow MSCs were optimised for the treatment of CIM using placental extract. FAPs in AMI transiently expressed p16INK4A on days 1 and 2 after injury and recruited phagocytic immune cells, whereas in CIM, p16INK4A expression in FAPs was low. Cellular senescence occurs during the natural maturation of the placenta. Therefore, we used human placental extract to induce p16INK4A expression in therapeutic human bone marrow MSCs in culture. Treatment of CIM with p16INK4A-expressing MSCs promoted tissue remodelling by transiently increasing the abundance of engrafted MSCs, inducing cellular senescence in innate FAPs, and recruiting phagocytic immune cells. MSCs may exert their effect by remodelling the chronic inflammatory environment via senescence-related regenerative processes. Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

The therapeutic benefits of mesenchymal stromal cells (MSCs) include treatment of chronic inflammation. However, given the short-lived engraftment of these cells in vivo, their therapeutic efficacy remains mysterious. Transient induction of cellular senescence contributes to activation of immune cells, which promotes clearance of damaged cells during tissue remodelling. This may occur in tissue-resident mesenchymal progenitor cells during regeneration. Elucidation of the role of senescence in tissue-resident mesenchymal progenitor cells during regeneration would provide insight into the profile of therapeutic MSCs for treatment of chronic inflammatory disease. We evaluated multipotent mesenchymal progenitor cells, termed fibro/adipogenic progenitors (FAPs), and immune cells in acute muscle injury (AMI) model mice and mice with myosin-induced experimental autoimmune myositis, a model of chronic inflammatory myopathy (CIM). Human bone marrow MSCs were optimised for the treatment of CIM using placental extract. FAPs in AMI transiently expressed p16INK4A on days 1 and 2 after injury and recruited phagocytic immune cells, whereas in CIM, p16INK4A expression in FAPs was low. Cellular senescence occurs during the natural maturation of the placenta. Therefore, we used human placental extract to induce p16INK4A expression in therapeutic human bone marrow MSCs in culture. Treatment of CIM with p16INK4A-expressing MSCs promoted tissue remodelling by transiently increasing the abundance of engrafted MSCs, inducing cellular senescence in innate FAPs, and recruiting phagocytic immune cells. MSCs may exert their effect by remodelling the chronic inflammatory environment via senescence-related regenerative processes. Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

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Muscle injury model:

... The precipitate was recovered via centrifugation for 10 min at 4 °C at 10,000g, dissolved in 0.5 M KCl, and stored at −80 °C. BALB/c mice (8 weeks old) were each immunised three times, at 1-week intervals, with 200 μl of an emulsion containing 1 mg myosin with 100 μg complete Freund's adjuvant (Chondrex Inc., Redmond, WA, USA), which was injected bilaterally into the hock (first immunisation) [20], tail base (second immunisation), and flank (third immunisation). One hour after the first immunisation, pertussis toxin (500 ng in 100 μl saline; List Biological Laboratories, Campbell, CA, USA) was intraperitoneally injected into each animal. 

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

Muscle injury model:

... The precipitate was recovered via centrifugation for 10 min at 4 °C at 10,000g, dissolved in 0.5 M KCl, and stored at −80 °C. BALB/c mice (8 weeks old) were each immunised three times, at 1-week intervals, with 200 μl of an emulsion containing 1 mg myosin with 100 μg complete Freund's adjuvant (Chondrex Inc., Redmond, WA, USA), which was injected bilaterally into the hock (first immunisation) [20], tail base (second immunisation), and flank (third immunisation). One hour after the first immunisation, pertussis toxin (500 ng in 100 μl saline; List Biological Laboratories, Campbell, CA, USA) was intraperitoneally injected into each animal. 

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

https://www.sciencedirect.com/science/article/pii/S2352396419303135https://www.sciencedirect.com/science/article/pii/S23523964193031352019-05-222019-05-2210.1016/j.ebiom.2019.05.01210.1016/j.ebiom.2019.05.012Pertussis Toxin from B. pertussis, Lyophilized in BufferPertussis Toxin from B. pertussis, Lyophilized in Bufferchikenji@sapmed.ac.jpchikenji@sapmed.ac.jp100;500;Activation;Acute;Animal;Autoimmune;Biological;Cell;Cellular;Culture;Disease;Efficacy;Environment;Experimental;Expressed;Expression;Flow Cytometry;Immune Cells;Induce;Induction;Inflammation;Inflammatory;List;List Biological;Muscle;Pertussis;Preparation;Regenerative;Sequence;Therapeutic;Tissue;Toxin;Treatment;Ebiomedicine100;500;Activation;Acute;Animal;Autoimmune;Biological;Cell;Cellular;Culture;Disease;Efficacy;Environment;Experimental;Expressed;Expression;Flow Cytometry;Immune Cells;Induce;Induction;Inflammation;Inflammatory;List;List Biological;Muscle;Pertussis;Preparation;Regenerative;Sequence;Therapeutic;Tissue;Toxin;Treatment;Ebiomedicine180180p16ink4a-expressing-mesenchymal-stromal-cells-restorep16ink4a-expressing-mesenchymal-stromal-cells-restore