Dysregulation of miR-185, miR-193a, and miR-450a in the skin are linked to the depressive phenotype

Erik Kaadt; Kristoffer Højgaard; Birgitte Mumm; Sofie Laage Christiansen; Heidi Kaastrup Müller; Christian Kroun Damgaard; Betina Elfving

doi:10.1016/j.pnpbp.2020.110052

Dysregulation of miR-185, miR-193a, and miR-450a in the skin are linked to the depressive phenotype

Erik Kaadt, Kristoffer Højgaard, Birgitte Mumm, Sofie Laage Christiansen, Heidi Kaastrup Müller, Christian Kroun Damgaard, Betina Elfving^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

8 Citationer (Scopus)

Abstract

BACKGROUND: Dysregulated microRNAs (miRNAs) in dermal fibroblasts of depressive subjects, indicate biomarker potential and can possibly aid clinical diagnostics. To overcome methodological challenges related to human experiments and fibroblast cultures, we here validate 38 miRNAs previously observed to be dysregulated in human fibroblasts from depressed subjects, in the skin of four distinct rat models of depression.

METHODS: In the presented study male rats from the adrenocorticotropic hormone (ACTH) model (n = 10/group), the chronic mild stress model (n = 10/group), Wistar Kyoto/Wistar Hannover rats (n = 10/group), and Flinders Resistant/Flinders Sensitive Line rats (n = 8/group) were included. Real-time qPCR was utilized to investigate miRNA alterations in flash-frozen skin-biopsies from the ear and fibroblast cultures.

RESULTS: In the ACTH rat model of depression, we identified nine dysregulated miRNAs in the skin and three in the fibroblasts. As the skin presented three times the amount of dysregulated miRNAs compared to the fibroblasts, skin instead of fibroblasts were continuously used for studies with the other rat models. In the skin from the four rat models of depression, 15 out of 38 miRNAs re-exhibited significant dysregulation in at least one of the rat models of depression and 67% were regulated in the same direction as in the human study. miR-450a and miR-193a presented dysregulation across rat models and miR-193a and miR-185 exhibited very strong dysregulation (30-fold and 50-fold, respectively). Lastly, an Ingenuity Pathway Analysis indicated functional overlap between dysregulated miRNAs, and common regulated pathways.

CONCLUSION: Flash-frozen skin is a valid alternative to fibroblast cultures as the skin appear to retain more of the miRNA dysregulation present in vivo. A sub-population of 15 miRNAs appear to be specific for the depressive phenotype, as they are dysregulated in both human depressed patients and distinct rat models of depression. We propose miR-450a, miR-185, and miR-193a as biomarker candidates of particular interest.

Originalsprog	Engelsk
Artikelnummer	110052
Tidsskrift	Progress in Neuro-Psychopharmacology & Biological Psychiatry
Vol/bind	104
Antal sider	10
ISSN	0278-5846
DOI	https://doi.org/10.1016/j.pnpbp.2020.110052
Status	Udgivet - jan. 2021

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10.1016/j.pnpbp.2020.110052

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@article{1781a7b8575741c0bf52e59188f77dbf,

title = "Dysregulation of miR-185, miR-193a, and miR-450a in the skin are linked to the depressive phenotype",

abstract = "BACKGROUND: Dysregulated microRNAs (miRNAs) in dermal fibroblasts of depressive subjects, indicate biomarker potential and can possibly aid clinical diagnostics. To overcome methodological challenges related to human experiments and fibroblast cultures, we here validate 38 miRNAs previously observed to be dysregulated in human fibroblasts from depressed subjects, in the skin of four distinct rat models of depression.METHODS: In the presented study male rats from the adrenocorticotropic hormone (ACTH) model (n = 10/group), the chronic mild stress model (n = 10/group), Wistar Kyoto/Wistar Hannover rats (n = 10/group), and Flinders Resistant/Flinders Sensitive Line rats (n = 8/group) were included. Real-time qPCR was utilized to investigate miRNA alterations in flash-frozen skin-biopsies from the ear and fibroblast cultures.RESULTS: In the ACTH rat model of depression, we identified nine dysregulated miRNAs in the skin and three in the fibroblasts. As the skin presented three times the amount of dysregulated miRNAs compared to the fibroblasts, skin instead of fibroblasts were continuously used for studies with the other rat models. In the skin from the four rat models of depression, 15 out of 38 miRNAs re-exhibited significant dysregulation in at least one of the rat models of depression and 67% were regulated in the same direction as in the human study. miR-450a and miR-193a presented dysregulation across rat models and miR-193a and miR-185 exhibited very strong dysregulation (30-fold and 50-fold, respectively). Lastly, an Ingenuity Pathway Analysis indicated functional overlap between dysregulated miRNAs, and common regulated pathways.CONCLUSION: Flash-frozen skin is a valid alternative to fibroblast cultures as the skin appear to retain more of the miRNA dysregulation present in vivo. A sub-population of 15 miRNAs appear to be specific for the depressive phenotype, as they are dysregulated in both human depressed patients and distinct rat models of depression. We propose miR-450a, miR-185, and miR-193a as biomarker candidates of particular interest.",

keywords = "Biomarkers, Depression, Skin, Stress, miRNA",

author = "Erik Kaadt and Kristoffer H{\o}jgaard and Birgitte Mumm and Christiansen, {Sofie Laage} and M{\"u}ller, {Heidi Kaastrup} and Damgaard, {Christian Kroun} and Betina Elfving",

year = "2021",

month = jan,

doi = "10.1016/j.pnpbp.2020.110052",

language = "English",

volume = "104",

journal = "Progress in Neuro-Psychopharmacology & Biological Psychiatry",

issn = "0278-5846",

publisher = "Elsevier Inc.",

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Dysregulation of miR-185, miR-193a, and miR-450a in the skin are linked to the depressive phenotype. / Kaadt, Erik ; Højgaard, Kristoffer ; Mumm, Birgitte et al.
I: Progress in Neuro-Psychopharmacology & Biological Psychiatry, Bind 104, 110052, 01.2021.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Dysregulation of miR-185, miR-193a, and miR-450a in the skin are linked to the depressive phenotype

AU - Kaadt, Erik

AU - Højgaard, Kristoffer

AU - Mumm, Birgitte

AU - Christiansen, Sofie Laage

AU - Müller, Heidi Kaastrup

AU - Damgaard, Christian Kroun

AU - Elfving, Betina

PY - 2021/1

Y1 - 2021/1

N2 - BACKGROUND: Dysregulated microRNAs (miRNAs) in dermal fibroblasts of depressive subjects, indicate biomarker potential and can possibly aid clinical diagnostics. To overcome methodological challenges related to human experiments and fibroblast cultures, we here validate 38 miRNAs previously observed to be dysregulated in human fibroblasts from depressed subjects, in the skin of four distinct rat models of depression.METHODS: In the presented study male rats from the adrenocorticotropic hormone (ACTH) model (n = 10/group), the chronic mild stress model (n = 10/group), Wistar Kyoto/Wistar Hannover rats (n = 10/group), and Flinders Resistant/Flinders Sensitive Line rats (n = 8/group) were included. Real-time qPCR was utilized to investigate miRNA alterations in flash-frozen skin-biopsies from the ear and fibroblast cultures.RESULTS: In the ACTH rat model of depression, we identified nine dysregulated miRNAs in the skin and three in the fibroblasts. As the skin presented three times the amount of dysregulated miRNAs compared to the fibroblasts, skin instead of fibroblasts were continuously used for studies with the other rat models. In the skin from the four rat models of depression, 15 out of 38 miRNAs re-exhibited significant dysregulation in at least one of the rat models of depression and 67% were regulated in the same direction as in the human study. miR-450a and miR-193a presented dysregulation across rat models and miR-193a and miR-185 exhibited very strong dysregulation (30-fold and 50-fold, respectively). Lastly, an Ingenuity Pathway Analysis indicated functional overlap between dysregulated miRNAs, and common regulated pathways.CONCLUSION: Flash-frozen skin is a valid alternative to fibroblast cultures as the skin appear to retain more of the miRNA dysregulation present in vivo. A sub-population of 15 miRNAs appear to be specific for the depressive phenotype, as they are dysregulated in both human depressed patients and distinct rat models of depression. We propose miR-450a, miR-185, and miR-193a as biomarker candidates of particular interest.

AB - BACKGROUND: Dysregulated microRNAs (miRNAs) in dermal fibroblasts of depressive subjects, indicate biomarker potential and can possibly aid clinical diagnostics. To overcome methodological challenges related to human experiments and fibroblast cultures, we here validate 38 miRNAs previously observed to be dysregulated in human fibroblasts from depressed subjects, in the skin of four distinct rat models of depression.METHODS: In the presented study male rats from the adrenocorticotropic hormone (ACTH) model (n = 10/group), the chronic mild stress model (n = 10/group), Wistar Kyoto/Wistar Hannover rats (n = 10/group), and Flinders Resistant/Flinders Sensitive Line rats (n = 8/group) were included. Real-time qPCR was utilized to investigate miRNA alterations in flash-frozen skin-biopsies from the ear and fibroblast cultures.RESULTS: In the ACTH rat model of depression, we identified nine dysregulated miRNAs in the skin and three in the fibroblasts. As the skin presented three times the amount of dysregulated miRNAs compared to the fibroblasts, skin instead of fibroblasts were continuously used for studies with the other rat models. In the skin from the four rat models of depression, 15 out of 38 miRNAs re-exhibited significant dysregulation in at least one of the rat models of depression and 67% were regulated in the same direction as in the human study. miR-450a and miR-193a presented dysregulation across rat models and miR-193a and miR-185 exhibited very strong dysregulation (30-fold and 50-fold, respectively). Lastly, an Ingenuity Pathway Analysis indicated functional overlap between dysregulated miRNAs, and common regulated pathways.CONCLUSION: Flash-frozen skin is a valid alternative to fibroblast cultures as the skin appear to retain more of the miRNA dysregulation present in vivo. A sub-population of 15 miRNAs appear to be specific for the depressive phenotype, as they are dysregulated in both human depressed patients and distinct rat models of depression. We propose miR-450a, miR-185, and miR-193a as biomarker candidates of particular interest.

KW - Biomarkers

KW - Depression

KW - Skin

KW - Stress

KW - miRNA

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U2 - 10.1016/j.pnpbp.2020.110052

DO - 10.1016/j.pnpbp.2020.110052

M3 - Journal article

C2 - 32738353

SN - 0278-5846

VL - 104

JO - Progress in Neuro-Psychopharmacology & Biological Psychiatry

JF - Progress in Neuro-Psychopharmacology & Biological Psychiatry

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ER -

Dysregulation of miR-185, miR-193a, and miR-450a in the skin are linked to the depressive phenotype

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