TY - JOUR
T1 - Mindin (SPON2) Is Essential for Cutaneous Fibrogenesis in a Mouse Model of Systemic Sclerosis
AU - Rana, Isha
AU - Kataria, Sunny
AU - Tan, Tuan Lin
AU - Hajam, Edries Yousaf
AU - Kashyap, Deepak Kumar
AU - Saha, Dyuti
AU - Ajnabi, Johan
AU - Paul, Sayan
AU - Jayappa, Shashank
AU - Ananthan, Akhil S.H.P.
AU - Kumar, Pankaj
AU - Zaarour, Rania F.
AU - Haarshaadri, J.
AU - Kansagara, Gaurav
AU - Rizvi, Abrar
AU - Zirmire, Ravindra K.
AU - Badarinath, Krithika
AU - Khedkar, Sneha Uday
AU - Chandra, Yogesh
AU - Samuel, Rekha
AU - George, Renu
AU - Danda, Debashish
AU - Jacob, Paul Mazhuvanchary
AU - Dey, Rakesh
AU - Dhandapany, Perundurai S.
AU - He, You Wen
AU - Varga, John
AU - Varghese, Shyni
AU - Jamora, Colin
N1 - Funding Information:
The authors would like to thank the members of Jamora laboratory for their critical review of the work and insightful discussions; Binita Dam, Syed Shahid Musvi, and Akshay Hegde for their technical assistance; and Ritoparna Hazra for designing the graphical model. This work was supported by core funds from inStem and grants from the Department of Biotechnology of the Government of India (BT/PR8738/AGR/36/770/2013 and BT/PR32539/BRB/10/1814/2019), the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (5R01AR053185-03), and the American Cancer Society (15457-RSG-08-164-01-DDC) to CJ. PSD is supported by the Department of Biotechnology/Wellcome Trust-Indian Alliance (IA/I/16/1/502367). IR and EYH were supported by the funding of the Indian Council of Medical Research (Senior Research Fellowship), and SK was partially supported by the National Centre for Biological Sciences. Animal studies were partially supported by the National Mouse Research Resource grant BT/PR5981/MED/31/181/2012;2013-2016;2018 and 102/IFD/SAN/5003/2017-2018 from the Department of Biotechnology. We thank the staff of the Bangalore Life Science Cluster Animal Care and Resource Centre and the Bangalore Life Science Cluster Central Imaging and Flow Cytometry Facility for technical assistance. This work was conducted in Bangalore, India. Conceptualization: CJ, SK, IR, TLT; Data Curation: IR, SK, TLT; Formal Analysis: SK, TLT, DKK, DS, PK, RD, SP, SJ, GK, AR, RKZ, SUK, PSD; Funding Acquisition: CJ; Investigation: IR, SK, TLT, EYH, DKK, DS, JA, ASHPA, RFZ, HJ, GK, KB, SUK, YC; Methodology: CJ, SK, IR, TLT; Project Administration: IR, SK, TLT, CJ, SV; Resources: RS, RG, DD, PMJ, PSD, YWH, JV, CJ, SV; Software: PK, RD, SP, SJ, SK; Supervision: CJ, SV, JV, PSD; Validation: IR, SK, TLT, EYH, DKK, DS, JA, ASHPA, RFZ, HJ, GK, AR, RKZ, SUK, YC; Visualization: SK; Writing - Original Draft Preparation: SK, IR, TLT, CJ; Writing - Review and Editing: SK, CJ, JV
Funding Information:
The authors would like to thank the members of Jamora laboratory for their critical review of the work and insightful discussions; Binita Dam, Syed Shahid Musvi, and Akshay Hegde for their technical assistance; and Ritoparna Hazra for designing the graphical model. This work was supported by core funds from inStem and grants from the Department of Biotechnology of the Government of India ( BT/PR8738/AGR/36/770/2013 and BT/PR32539/BRB/10/1814/2019 ), the National Institutes of Health / National Institute of Arthritis and Musculoskeletal and Skin Diseases ( 5R01AR053185-03 ), and the American Cancer Society ( 15457-RSG-08-164-01-DDC ) to CJ. PSD is supported by the Department of Biotechnology / Wellcome Trust-Indian Alliance ( IA/I/16/1/502367 ). IR and EYH were supported by the funding of the Indian Council of Medical Research (Senior Research Fellowship), and SK was partially supported by the National Centre for Biological Sciences . Animal studies were partially supported by the National Mouse Research Resource grant BT/PR5981/MED/31/181/2012;2013-2016;2018 and 102/IFD/SAN/5003/2017-2018 from the Department of Biotechnology. We thank the staff of the Bangalore Life Science Cluster Animal Care and Resource Centre and the Bangalore Life Science Cluster Central Imaging and Flow Cytometry Facility for technical assistance. This work was conducted in Bangalore, India.
Publisher Copyright:
© 2022 The Authors
PY - 2023/5
Y1 - 2023/5
N2 - Systemic sclerosis is a fibrotic disease that initiates in the skin and progresses to internal organs, leading to a poor prognosis. Unraveling the etiology of a chronic, multifactorial disease such as systemic sclerosis has been aided by various animal models that recapitulate certain aspects of the human pathology. We found that the transcription factor SNAI1 is overexpressed in the epidermis of patients with systemic sclerosis, and a transgenic mouse recapitulating this expression pattern is sufficient to induce many clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin (SPON2) in fibrogenesis. Mindin is produced by SNAI1 transgenic skin keratinocytes and aids fibrogenesis by inducing early inflammatory cytokine production and collagen secretion in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis.
AB - Systemic sclerosis is a fibrotic disease that initiates in the skin and progresses to internal organs, leading to a poor prognosis. Unraveling the etiology of a chronic, multifactorial disease such as systemic sclerosis has been aided by various animal models that recapitulate certain aspects of the human pathology. We found that the transcription factor SNAI1 is overexpressed in the epidermis of patients with systemic sclerosis, and a transgenic mouse recapitulating this expression pattern is sufficient to induce many clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin (SPON2) in fibrogenesis. Mindin is produced by SNAI1 transgenic skin keratinocytes and aids fibrogenesis by inducing early inflammatory cytokine production and collagen secretion in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis.
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U2 - 10.1016/j.jid.2022.10.011
DO - 10.1016/j.jid.2022.10.011
M3 - Article
C2 - 36528128
AN - SCOPUS:85147371481
SN - 0022-202X
VL - 143
SP - 699-710.e10
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 5
ER -