Dataset Information

Fetal immunomodulatory environment following cartilage injury – the key to cartilage regeneration?

ABSTRACT: Fetal cartilage fully regenerates following injury while in adult mammals cartilage injury leads to osteoarthritis (OA). OA is characterized by cartilage breakdown and joint inflammation and associated with significant pain and socioeconomic costs. As no clinically satisfactory treatment is available to date, disease-modifying therapies aimed to achieve cartilage regeneration are urgently required. The inherent regeneration potential of fetal individuals may hold answers to this unmet need. Therefore, to characterize the differences in fetal and adult response to cartilage injury, we carried out histology and comprehensive proteome analyses on fetal (day 80/150-day gestation) and adult cartilage samples one (fetal samples) and three (adult and fetal samples) days after surgical induction of a full-thickness cartilage lesion. In addition, proteins secreted by inflamed fetal MSCs in vitro were compared with the in vivo response to injury to evaluate their therapeutic potential. Histology of synovial samples revealed the presence of neutrophils one day post injury (p.i.) and an influx of macrophages into the subsynovial tissue on day 3 p.i. in fetal samples. In contrast, adult synovial samples showed invasion of neutrophils on day 3 p.i. Activation and migration of Iba1+- macrophages of the synovial lining was observed both in fetal and adult animals. Comparative mass spectrometry revealed 57 proteins significantly up-regulated (> 2FC, FDR<0.05), and 67 proteins significantly down-regulated (<-2 FC) upon injury in adults. Neutrophil-related proteins and acute phase proteins were the two major upregulated protein groups in adult cartilage following injury compared to fetal sheep. In contrast, several immunomodulating proteins and growth factors were significantly higher expressed in the fetus than the adult. Comparison of the in vitro MSCs with the in vivo fetal proteome revealed shared upregulation of 17 proteins, which were considered to be of potential therapeutic interest. The results of this study support our molecular understanding of successful fetal cartilage healing and new therapeutic strategies to induce regeneration in adult articular cartilage by modulating the inflammatory environment. The shared protein upregulation in fetal cartilage in vivo and in fetal MSCS during in vitro inflammation supports the possible therapeutic potential of these factors in specific and fetal MSCs in general.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Ovis Aries

TISSUE(S): Cartilage, Stem Cell, Cell Culture

SUBMITTER: Christopher Gerner

LAB HEAD: Christopher Gerner

PROVIDER: PXD027486 | Pride | 2022-02-17

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	MQ_fMSC_peak_andromeda.zip	Other
	MQ_fMSC_search_txt.zip	Other
	MQ_in-vivo_peak_andromeda.zip	Other
	MQ_in-vivo_search_txt.zip	Other
	Sheep_1_AiN01_inj_1.raw	Raw

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Fetal Immunomodulatory Environment Following Cartilage Injury-The Key to CARTILAGE Regeneration?

Ribitsch Iris I Bileck Andrea A Egerbacher Monika M Gabner Simone S Mayer Rupert L RL Janker Lukas L Gerner Christopher C Jenner Florien F

International journal of molecular sciences 20211130 23

Fetal cartilage fully regenerates following injury, while in adult mammals cartilage injury leads to osteoarthritis (OA). Thus, in this study, we compared the in vivo injury response of fetal and adult ovine articular cartilage histologically and proteomically to identify key factors of fetal regeneration. In addition, we compared the secretome of fetal ovine mesenchymal stem cells (MSCs) in vitro with injured fetal cartilage to identify potential MSC-derived therapeutic factors. Cartilage injur ...[more]

PMID: 34884768

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Project description:Cartilage plays a fundamental role in the development of the human skeleton. Early in embryogenesis, mesenchymal cells condense and differentiate to chondrocytes to shape the early skeleton. Subsequently, the cartilage anlagen differentiate to form the growth plates, which are responsible for linear bone growth, and the articular chondrocytes, which facilitate joint function. However, despite the multiplicity of roles of cartilage during human fetal life, surprisingly little is known about its transcriptome. To address this, a whole genome microarray expression profile was generated using RNA isolated from 18-22 week human distal femur fetal cartilage and compared with a database of control normal human tissues aggregated at UCLA, termed CELSIUS. From the wealth of data, 161 cartilage-selective genes were identified, defined as genes significantly expressed in cartilage with low expression and little variation across a panel of 34 non-cartilage tissues. Among these 161 genes were cartilage-specific genes such as collagen genes and 25 genes which have been associated with skeletal phenotypes in humans and/or mice. Many of the other cartilage-selective genes do not have established roles in cartilage or are novel, unannotated genes. Quantitative RT-PCR confirmed the unique pattern of gene expression observed by microarray analysis. Defining the gene expression pattern for cartilage has identified new genes that may contribute to human skeletogenesis as well as provided further candidate genes for skeletal dysplasias. The data suggest that fetal cartilage is a complex and transcriptionally active tissue and demonstrate that the set of genes selectively expressed in the tissue has been greatly underestimated. Experiment Overall Design: RNA from 7 normal fetal cartilage samples was isolated. 5 samples were run in duplicate on U133 2.0 arrays, while 2 were run on U133A and U133B subsets. In brief, cartilage selective genes were identified by comparing 5 normal cartilage samples (GSM149638,GSM149639 ,GSM149640,GSM149641 ,GSM149642) to normal tissue expression profiles found on CELCIUS at UCLA. Genes which were found expressed at significantly higher levels were validated for their elevated and specific expression using the three platforms. The 9 validation arrays are: 5 U133 2.0 (GSM149643 ,GSM149644 ,GSM149645 ,GSM149646,GSM149647), 2 U133A (GSM149651, GSM149652), 2 U133B (GSM149653, GSM149654)