Cellular features of localized microenvironments in human meniscal degeneration: a single-cell transcriptomic study
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Evaluation Summary:
This paper will be of interest to researchers studying meniscus homeostasis and knee osteoarthritis. It uncovers distinct subtypes of cell populations in inner and outer part of human meniscus using single-cell RNA sequencing. In particular, this work further identifies how alterations in meniscal cell populations may contribute to inflammation and osteoarthritis and thus serves as a resource paper for the field.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
Musculoskeletal tissue degeneration impairs the life quality and function of many people. Meniscus degeneration is a major origin of knee osteoarthritis and a common threat to athletic ability, but its cellular mechanism remains elusive.
Methods:
We built a cell atlas of 12 healthy or degenerated human meniscus samples from the inner and outer meniscal zones of 8 patients using scRNA-seq to investigate meniscal microenvironment homeostasis and its changes in the degeneration process and verified findings with immunofluorescent imaging.
Results:
We identified and localized cell types in inner and outer meniscus and found new chondrocyte subtypes associated with degeneration. The observations suggested understandings on how cellular compositions, functions, and interactions participated in degeneration, and on the possible loop-like interactions among extracellular matrix disassembly, angiogenesis, and inflammation in driving the degeneration.
Conclusions:
The study provided a rich resource reflecting variations in the meniscal microenvironment during degeneration and suggested new cell subtypes as potential therapeutic targets. The hypothesized mechanism could also be a general model for other joint degenerations.
Funding:
The National Natural Science Foundation of China (81972123, 82172508, 62050178, 61721003), the National Key Research and Development Program of China (2021YFF1200901), Fundamental Research Funds for the Central Universities (2015SCU04A40); The Innovative Spark Project of Sichuan University (2018SCUH0034); Sichuan Science and Technology Program (2020YFH0075); Chengdu Science and Technology Bureau Project (2019-YF05-00090-SN); 1.3.5 Project for Disciplines of Excellence of West China Hospital Sichuan University (ZYJC21030, ZY2017301); 1.3.5 Project for Disciplines of Excellence – Clinical Research Incubation Project, West China Hospital, Sichuan University (2019HXFH039).
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Evaluation Summary:
This paper will be of interest to researchers studying meniscus homeostasis and knee osteoarthritis. It uncovers distinct subtypes of cell populations in inner and outer part of human meniscus using single-cell RNA sequencing. In particular, this work further identifies how alterations in meniscal cell populations may contribute to inflammation and osteoarthritis and thus serves as a resource paper for the field.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The transcriptome of the cells of the human meniscus have been studied in bulk or superficially via single cell methods. In this study, the authors profile the types of cells present in the normal/healthy human meniscus as well as samples from degenerative menisci using single cell RNA seq. Using pre-existing analysis packages for single cell RNA seq data, they infer the roll of the various cell type clusters that they have identified and posit which cells interact with which cells as part of the healthy meniscus and in disease. They have developed an on-line viewer to facilitate use of these data by other research groups.
Strengths: The data has been rigorously collected and appropriate quality control steps have been implemented to ensure the veracity of the data. The result is a robust data set. This is …
Reviewer #1 (Public Review):
The transcriptome of the cells of the human meniscus have been studied in bulk or superficially via single cell methods. In this study, the authors profile the types of cells present in the normal/healthy human meniscus as well as samples from degenerative menisci using single cell RNA seq. Using pre-existing analysis packages for single cell RNA seq data, they infer the roll of the various cell type clusters that they have identified and posit which cells interact with which cells as part of the healthy meniscus and in disease. They have developed an on-line viewer to facilitate use of these data by other research groups.
Strengths: The data has been rigorously collected and appropriate quality control steps have been implemented to ensure the veracity of the data. The result is a robust data set. This is coupled with the on line viewer portal they have created, allowing the data to be available in the public domain. Further, having this tool is a huge resource as it means that the end user does not need to have advanced programing skills to be able to use it. Some of the RNA seq results have been validated via in situ and immunofluorescence. The authors have compared their results to data already published and discuss disagreements.
Weaknesses: Some of the conclusions are very over reaching. The function of clusters, the role of cells and the interactions between cells are all inferred results based on data analyses. These results gave not been experimentally validated.
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Reviewer #2 (Public Review):
In the current study, Weili Fu et al. revealed unique cell populations in inner and outer zone of human meniscus using single-cell RNA sequencing and bioinformatic approaches. The authors identified five conserved chondrocyte populations and two pericyte-like cell (PCL) subsets between inner and outer zone menisci as well as across normal and osteoarthritic conditions. They also observed that there is increased FNDC1-enriched chondrocyte 2 (Ch2) and PRG4-enriched Ch3 chondrocyte populations in degenerated meniscus, while CHAD-enriched Ch1 is the predominate chondrocyte subset along with both PCL populations in normal meniscus. Analysis of differentially expressed genes between degenerated and healthy meniscus indeed correspond to the cell population changes resulting from disease progression. Spatial …
Reviewer #2 (Public Review):
In the current study, Weili Fu et al. revealed unique cell populations in inner and outer zone of human meniscus using single-cell RNA sequencing and bioinformatic approaches. The authors identified five conserved chondrocyte populations and two pericyte-like cell (PCL) subsets between inner and outer zone menisci as well as across normal and osteoarthritic conditions. They also observed that there is increased FNDC1-enriched chondrocyte 2 (Ch2) and PRG4-enriched Ch3 chondrocyte populations in degenerated meniscus, while CHAD-enriched Ch1 is the predominate chondrocyte subset along with both PCL populations in normal meniscus. Analysis of differentially expressed genes between degenerated and healthy meniscus indeed correspond to the cell population changes resulting from disease progression. Spatial location of some cell types was validated. The analysis of cell-cell crosstalk suggests that endothelial cells, immune cells and chondrocytes may form a vicious cycle leading to meniscal degeneration. The authors also provided an excellent online cell browser to share their findings to the research community. Overall, the conclusions of this paper are mostly supported by data, but some aspects of statements and data analysis need to be clarified and further extended.
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Reviewer 3 (Public Review):
This is an interesting study that describes a single cell RNAseq analysis of human menisci. The study describes cell profiling of healthy and degenerated menisci divided into two zones, inner and outer meniscus.
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