Cell and transcriptomic diversity of infrapatellar fat pad during knee osteoarthritis

Hayley Peters; Pratibha Potla; Jason S Rockel; Teodora Tockovska; Chiara Pastrello; Igor Jurisica; Keemo Delos Santos; Shabana Vohra; Noah Fine; Starlee Lively; Kim Perry; Nikita Looby; Sheng Han Li; Vinod Chandran; Katrina Hueniken; Paramvir Kaur; Anthony V Perruccio; Nizar N Mahomed; Raja Rampersaud; Khalid Syed; Eric Gracey; Roman Krawetz; Matthew B Buechler; Rajiv Gandhi; Mohit Kapoor

doi:10.1136/ard-2024-225928

Cell and transcriptomic diversity of infrapatellar fat pad during knee osteoarthritis

Ann Rheum Dis. 2024 Oct 15:ard-2024-225928. doi: 10.1136/ard-2024-225928. Online ahead of print.

Authors

Hayley Peters^{1

2

3}, Pratibha Potla^{1

3}, Jason S Rockel^{1

3}, Teodora Tockovska^{1

4}, Chiara Pastrello^{1

3}, Igor Jurisica^{1

3

5}, Keemo Delos Santos^{1

3}, Shabana Vohra^{1

3}, Noah Fine^{1

3}, Starlee Lively^{1

3}, Kim Perry^{1

3}, Nikita Looby^{1

3

6}, Sheng Han Li^{2

3

6}, Vinod Chandran^{1

2

3

6

7}, Katrina Hueniken^{1

3}, Paramvir Kaur^{1

3}, Anthony V Perruccio^{1

3

8

9}, Nizar N Mahomed^{1

3

8}, Raja Rampersaud^{1

3

8}, Khalid Syed^{1

3

8}, Eric Gracey^{10

11}, Roman Krawetz¹², Matthew B Buechler¹³, Rajiv Gandhi^{1

2

3

8}, Mohit Kapoor^{14

2

3

8}

Affiliations

¹ Division of Orthopaedics, Osteoarthritis Research Program, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.
² Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
³ Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
⁴ Bioinformatics and HPC Core, Princess Margaret Cancer Research Tower, University Health Network, Toronto, Ontario, Canada.
⁵ Departments of Medical Biophysics and Computer Science, and Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
⁶ Division of Rheumatology, Psoriatic Arthritis Research Program, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.
⁷ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
⁹ Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Molecular Immunology and Inflammation Unit, VIB Centre for Inflammation Research, Ghent University, Ghent, Belgium.
¹¹ Department of Rheumatology, University Hospital Ghent, Ghent, Belgium.
¹² McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
¹³ Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
¹⁴ Division of Orthopaedics, Osteoarthritis Research Program, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada mkapoor@uhnresearch.ca.

PMID: 39375009
DOI: 10.1136/ard-2024-225928

Abstract

Objectives: In this study, we employ a multiomic approach to identify major cell types and subsets, and their transcriptomic profiles within the infrapatellar fat pad (IFP), and to determine differences in the IFP based on knee osteoarthritis (KOA), sex and obesity status.

Methods: Single-nucleus RNA sequencing of 82 924 nuclei from 21 IFPs (n=6 healthy control and n=15 KOA donors), spatial transcriptomics and bioinformatic analyses were used to identify contributions of the IFP to KOA. We mapped cell subclusters from other white adipose tissues using publicly available literature. The diversity of fibroblasts within the IFP was investigated by bioinformatic analyses, comparing by KOA, sex and obesity status. Metabolomics was used to further explore differences in fibroblasts by obesity status.

Results: We identified multiple subclusters of fibroblasts, macrophages, adipocytes and endothelial cells with unique transcriptomic profiles. Using spatial transcriptomics, we resolved distributions of cell types and their transcriptomic profiles and computationally identified putative cell-cell communication networks. Furthermore, we identified transcriptomic differences in fibroblasts from KOA versus healthy control donor IFPs, female versus male KOA-IFPs and obese versus normal body mass index (BMI) KOA-IFPs. Finally, using metabolomics, we defined differences in metabolite levels in supernatants of naïve, profibrotic stimuli-treated and proinflammatory stimuli-treated fibroblasts from obese compared to normal BMI KOA-IFPs.

Conclusions: Overall, by employing a multiomic approach, this study provides the first comprehensive map of the cellular and transcriptomic diversity of human IFP and identifies IFP fibroblasts as key cells contributing to transcriptomic and metabolic differences related to KOA disease, sex or obesity.

Keywords: Arthritis; Fibroblasts; Osteoarthritis; Osteoarthritis, Knee; Risk Factors.