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A dichotomous response to chronic fetal hypoxia preprograms aging already during kidney development

ABSTRACT: Hypoxia-induced intrauterine growth restriction increases the risk for chronic diseases in adults, affecting more than 140 million high altitude residents worldwide. Still, not much is known about the fetal mechanisms that prone these individuals to disease. Using bottom-up proteomics and the kidney as a readout, we delineated a dichotomous response to chronic hypoxic stress, comprising mechanisms that promote survival, but also induce premature senescence. Combined outcome is the manifestation of a predetermined aging phenotype already during fetal development. This aging phenotype is associated with a characteristic biomarker profile in tissue and blood serum samples, exploitable for targeting and monitoring disease.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Kidney

SUBMITTER: Christopher Gerner

LAB HEAD: Christopher Gerner

PROVIDER: PXD018999 | Pride | 2022-01-13

REPOSITORIES: Pride

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			Action	DRS
	mouse_kidney_hypoxic_1_fraction_1_replicate_1.mzML	Mzml
	mouse_kidney_hypoxic_1_fraction_1_replicate_1.mzid.gz	Mzid
	mouse_kidney_hypoxic_1_fraction_1_replicate_1.pride.mgf.gz	Mgf
	mouse_kidney_hypoxic_1_fraction_1_replicate_1.raw	Raw
	mouse_kidney_hypoxic_1_fraction_1_replicate_2.mzML	Mzml

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Project description: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.

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A dichotomous response to chronic fetal hypoxia preprograms aging already during kidney development

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