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

被引：25

作者：

Chikenji, Takako S. ^{[1
]}

Saito, Yuki ^{[1
]}

Konari, Naoto ^{[1
]}

Nakano, Masako ^{[1
]}

Mizue, Yuka ^{[1
]}

Otani, Miho ^{[1
]}

Fujimiya, Mineko ^{[1
]}

机构：

[1] Sapporo Med Univ, Dept Anat, Sch Med, Sapporo, Hokkaido 0608556, Japan

来源：

EBIOMEDICINE | 2019年 / 44卷

关键词：

Mesenchymal stromal cell; Regenerative medicine; Tissue remodelling; Senescence; Chronic inflammation; REGULATORY T-CELLS; STEM-CELLS; IN-VIVO; CELLULAR SENESCENCE; SUPPRESSOR-CELLS; EXPRESSION; FIBROSIS; INJURY; MACROPHAGES; P16(INK4A);

D O I：

10.1016/j.ebiom.2019.05.012

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: 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. Methods: 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 auto-immune myositis, a model of chronic inflammatory myopathy (CIM). Human bone marrow MSCs were optimised for the treatment of CIM using placental extract. Finding: FAPs in AMI transiently expressed p16(INK4A) on days 1 and 2 after injury and recruited phagocytic immune cells, whereas in CIM, p16(INK4A) expression in FAPs was low. Cellular senescence occurs during the natural maturation of the placenta. Therefore, we used human placental extract to induce p16(INK4A) expression in therapeutic human bone marrow MSCs in culture. Treatment of CIM with p16(INK4A)-expressing MSCs promoted tissue remodelling by transiently increasing the abundance of engrafted MSCs, inducing cellular senescence in innate FAPs, and recruiting phagocytic immune cells. Interpretation: MSCs may exert their effect by remodelling the chronic inflammatory environment via senescence-related regenerative processes. (C) 2019 The Authors. Published by Elsevier B.V.

引用

页码：86 / 97

页数：12

共 51 条

[11] Injury-Induced Senescence Enables In Vivo Reprogramming in Skeletal Muscle [J].

Chiche, Aurelie ;

Le Roux, Isabelle ;

von Joest, Mathieu ;

Sakai, Hiroshi ;

Aguin, Sabela Bua ;

Cazin, Coralie ;

Salam, Rana ;

Fiette, Laurence ;

Alegria, Olinda ;

Flamant, Patricia ;

Tajbakhsh, Shahragim ;

Li, Han .

CELL STEM CELL, 2017, 20 (03) :407-+

[12] Senescence and apoptosis: dueling or complementary cell fates? [J].

Childs, Bennett G. ;

Baker, Darren J. ;

Kirkland, James L. ;

Campisi, Judith ;

van Deursen, Jan M. .

EMBO REPORTS, 2014, 15 (11) :1139-1153

[13] Cell fusion induced by ERVWE1 or measles virus causes cellular senescence [J].

Chuprin, Anna ;

Gal, Hilah ;

Biron-Shental, Tal ;

Biran, Anat ;

Amiel, Aliza ;

Rozenblatt, Shmuel ;

Krizhanovsky, Valery .

GENES & DEVELOPMENT, 2013, 27 (21) :2356-2366

[14] p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages [J].

Cudejko, Celine ;

Wouters, Kristiaan ;

Fuentes, Lucia ;

Hannou, Sarah Anissa ;

Paquet, Charlotte ;

Bantubungi, Kadiombo ;

Bouchaert, Emmanuel ;

Vanhoutte, Jonathan ;

Fleury, Sebastien ;

Remy, Patrick ;

Tailleux, Anne ;

Chinetti-Gbaguidi, Giulia ;

Dombrowicz, David ;

Staels, Bart ;

Paumelle, Rejane .

BLOOD, 2011, 118 (09) :2556-2566

[15] Inflammatory Muscle Diseases [J].

Dalakas, Marinos C. .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 372 (18) :1734-1747

[16] Monocyte and Macrophage Plasticity in Tissue Repair and Regeneration [J].

Das, Amitava ;

Sinha, Mithun ;

Datta, Soma ;

Abas, Motaz ;

Chaffee, Scott ;

Sen, Chandan K. ;

Roy, Sashwati .

AMERICAN JOURNAL OF PATHOLOGY, 2015, 185 (10) :2596-2606

[17] An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA [J].

Demaria, Marco ;

Ohtani, Naoko ;

Youssef, Sameh A. ;

Rodier, Francis ;

Toussaint, Wendy ;

Mitchell, James R. ;

Laberge, Remi-Martin ;

Vijg, Jan ;

Van Steeg, Harry ;

Dolle, Martijn E. T. ;

Hoeijmakers, Jan H. J. ;

de Bruin, Alain ;

Hara, Eiji ;

Campisi, Judith .

DEVELOPMENTAL CELL, 2014, 31 (06) :722-733

[18] Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities [J].

Galipeau, Jacques ;

Sensebe, Luc .

CELL STEM CELL, 2018, 22 (06) :824-833

[19] Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation [J].

Galleu, Antonio ;

Riffo-Vasquez, Yanira ;

Trento, Cristina ;

Lomas, Cara ;

Dolcetti, Luigi ;

Cheung, Tik Shing ;

von Bonin, Malte ;

Barbieri, Laura ;

Halai, Krishma ;

Ward, Sophie ;

Weng, Ling ;

Chakraverty, Ronjon ;

Lombardi, Giovanna ;

Watt, Fiona M. ;

Orchard, Kim ;

Marks, David I. ;

Apperley, Jane ;

Bornhauser, Martin ;

Walczak, Henning ;

Bennett, Clare ;

Dazzi, Francesco .

SCIENCE TRANSLATIONAL MEDICINE, 2017, 9 (416)

[20] Comparative Study of Injury Models for Studying Muscle Regeneration in Mice [J].

Hardy, David ;

Besnard, Aurore ;

Latil, Mathilde ;

Jouvion, Gregory ;

Briand, David ;

Thepenier, Cedric ;

Pascal, Quentin ;

Guguin, Aurelie ;

Gayraud-Morel, Barbara ;

Cavaillon, Jean-Marc ;

Tajbakhsh, Shahragim ;

Rocheteau, Pierre ;

Chretien, Fabrice .

PLOS ONE, 2016, 11 (01)

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