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Article: Cell non-autonomous regulation of cerebrovascular aging processes by the somatotropic axis.

Bickel, Marisa A / Csik, Boglarka / Gulej, Rafal / Ungvari, Anna / Nyul-Toth, Adam / Conley, Shannon M

2023 Volume 14, Page(s) 1087053

Abstract: Age-related cerebrovascular pathologies, ranging from cerebromicrovascular functional and structural alterations to large vessel atherosclerosis, promote the genesis of vascular cognitive impairment and dementia (VCID) and exacerbate Alzheimer's disease. ...

Abstract	Age-related cerebrovascular pathologies, ranging from cerebromicrovascular functional and structural alterations to large vessel atherosclerosis, promote the genesis of vascular cognitive impairment and dementia (VCID) and exacerbate Alzheimer's disease. Recent advances in geroscience, including results from studies on heterochronic parabiosis models, reinforce the hypothesis that cell non-autonomous mechanisms play a key role in regulating cerebrovascular aging processes. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) exert multifaceted vasoprotective effects and production of both hormones is significantly reduced in aging. This brief overview focuses on the role of age-related GH/IGF-1 deficiency in the development of cerebrovascular pathologies and VCID. It explores the mechanistic links among alterations in the somatotropic axis, specific macrovascular and microvascular pathologies (including capillary rarefaction, microhemorrhages, impaired endothelial regulation of cerebral blood flow, disruption of the blood brain barrier, decreased neurovascular coupling, and atherogenesis) and cognitive impairment. Improved understanding of cell non-autonomous mechanisms of vascular aging is crucial to identify targets for intervention to promote cerebrovascular and brain health in older adults.
MeSH term(s)	Humans ; Aged ; Insulin-Like Growth Factor I/metabolism ; Brain/metabolism ; Cognitive Dysfunction/etiology ; Cerebrovascular Circulation/physiology ; Dementia, Vascular
Chemical Substances	Insulin-Like Growth Factor I (67763-96-6)
Language	English
Publishing date	2023-01-23
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1087053
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Article ; Online: Adherent but Not Suspension-Cultured Embryoid Bodies Develop into Laminated Retinal Organoids.

Radojevic, Bojana / Conley, Shannon M / Bennett, Lea D

Journal of developmental biology

2021 Volume 9, Issue 3

Abstract: Human induced pluripotent stem cells (iPSCs) are differentiated into three-dimensional (3D) retinal organoids to study retinogenesis and diseases that would otherwise be impossible. The complexity and low yield in current protocols remain a technical ... ...

Abstract	Human induced pluripotent stem cells (iPSCs) are differentiated into three-dimensional (3D) retinal organoids to study retinogenesis and diseases that would otherwise be impossible. The complexity and low yield in current protocols remain a technical challenge, particularly for inexperienced personnel. Differentiation protocols require labor-intensive and time-consuming dissection of optic vesicles (OVs). Here we compare this method with a suspension method of developing retinal organoids. iPSCs were differentiated with standard protocols but the suspension-grown method omitted the re-plating of embryoid bodies and dissection of OVs. All other media and treatments were identical between developmental methods. Developmental maturation was evaluated with RT-qPCR and immunocytochemistry. Dissection- and suspension-derived retinal organoids displayed temporal biogenesis of retinal cell types. Differences in retinal organoids generated by the two methods of differentiation included temporal developmental and the organization of neural retina layers. Retinal organoids grown in suspension showed delayed development and disorganized retinal layers compared to the dissected retinal organoids. We found that omitting the re-plating of EBs to form OVs resulted in numerous OVs that were easy to identify and matured along a retinal lineage. While more efficient, the suspension method led to retinal organoids with disorganized retinal layers compared to those obtained using conventional dissection protocols.
Language	English
Publishing date	2021-09-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720870-9
ISSN	2221-3759 ; 2221-3759
ISSN (online)	2221-3759
ISSN	2221-3759
DOI	10.3390/jdb9030038
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Article ; Online: Adherent but Not Suspension-Cultured Embryoid Bodies Develop into Laminated Retinal Organoids

Bojana Radojevic / Shannon M. Conley / Lea D. Bennett

Journal of Developmental Biology, Vol 9, Iss 38, p

2021 Volume 38

Abstract	Human induced pluripotent stem cells (iPSCs) are differentiated into three-dimensional (3D) retinal organoids to study retinogenesis and diseases that would otherwise be impossible. The complexity and low yield in current protocols remain a technical challenge, particularly for inexperienced personnel. Differentiation protocols require labor-intensive and time-consuming dissection of optic vesicles (OVs). Here we compare this method with a suspension method of developing retinal organoids. iPSCs were differentiated with standard protocols but the suspension-grown method omitted the re-plating of embryoid bodies and dissection of OVs. All other media and treatments were identical between developmental methods. Developmental maturation was evaluated with RT-qPCR and immunocytochemistry. Dissection- and suspension-derived retinal organoids displayed temporal biogenesis of retinal cell types. Differences in retinal organoids generated by the two methods of differentiation included temporal developmental and the organization of neural retina layers. Retinal organoids grown in suspension showed delayed development and disorganized retinal layers compared to the dissected retinal organoids. We found that omitting the re-plating of EBs to form OVs resulted in numerous OVs that were easy to identify and matured along a retinal lineage. While more efficient, the suspension method led to retinal organoids with disorganized retinal layers compared to those obtained using conventional dissection protocols.
Keywords	human retinal organoid ; retinogenesis ; differentiation ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Microvascular smooth muscle cells exhibit divergent phenotypic switching responses to platelet-derived growth factor and insulin-like growth factor 1.

Bickel, Marisa A / Sherry, David M / Bullen, Elizabeth C / Vance, Michaela L / Jones, Ken L / Howard, Eric W / Conley, Shannon M

Microvascular research

2023 Volume 151, Page(s) 104609

Abstract: Objective: Vascular smooth muscle cell (VSMC) phenotypic switching is critical for normal vessel formation, vascular stability, and healthy brain aging. Phenotypic switching is regulated by mediators including platelet derived growth factor (PDGF)-BB, ... ...

Abstract	Objective: Vascular smooth muscle cell (VSMC) phenotypic switching is critical for normal vessel formation, vascular stability, and healthy brain aging. Phenotypic switching is regulated by mediators including platelet derived growth factor (PDGF)-BB, insulin-like growth factor (IGF-1), as well as transforming growth factor-β (TGF-β) and endothelin-1 (ET-1), but much about the role of these factors in microvascular VSMCs remains unclear. Methods: We used primary rat microvascular VSMCs to explore PDGF-BB- and IGF-1-induced phenotypic switching. Results: PDGF-BB induced an early proliferative response, followed by formation of polarized leader cells and rapid, directionally coordinated migration. In contrast, IGF-1 induced cell hypertrophy, and only a small degree of migration by unpolarized cells. TGF-β and ET-1 selectively inhibit PDGF-BB-induced VSMC migration primarily by repressing migratory polarization and formation of leader cells. Contractile genes were downregulated by both growth factors, while other genes were differentially regulated by PDGF-BB and IGF-1. Conclusions: These studies indicate that PDGF-BB and IGF-1 stimulate different types of microvascular VSMC phenotypic switching characterized by different modes of cell migration. Our studies are consistent with a chronic vasoprotective role for IGF-1 in VSMCs in the microvasculature while PDGF is more involved in VSMC proliferation and migration in response to acute activities such as neovascularization. Better understanding of the nuances of the phenotypic switching induced by these growth factors is important for our understanding of a variety of microvascular diseases.
MeSH term(s)	Rats ; Animals ; Becaplermin/pharmacology ; Proto-Oncogene Proteins c-sis/pharmacology ; Proto-Oncogene Proteins c-sis/metabolism ; Insulin-Like Growth Factor I/pharmacology ; Insulin-Like Growth Factor I/metabolism ; Transforming Growth Factor beta/metabolism ; Myocytes, Smooth Muscle ; Cell Proliferation ; Cell Movement ; Cells, Cultured
Chemical Substances	Becaplermin (1B56C968OA) ; Proto-Oncogene Proteins c-sis ; Insulin-Like Growth Factor I (67763-96-6) ; Transforming Growth Factor beta
Language	English
Publishing date	2023-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80307-8
ISSN	1095-9319 ; 0026-2862
ISSN (online)	1095-9319
ISSN	0026-2862
DOI	10.1016/j.mvr.2023.104609
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Article ; Online: Vascular smooth muscle cell-specific Igf1r deficiency exacerbates the development of hypertension-induced cerebral microhemorrhages and gait defects.

Miller, Lauren R / Bickel, Marisa A / Vance, Michaela L / Vaden, Hannah / Nagykaldi, Domonkos / Nyul-Toth, Adam / Bullen, Elizabeth C / Gautam, Tripti / Tarantini, Stefano / Yabluchanskiy, Andriy / Kiss, Tamas / Ungvari, Zoltan / Conley, Shannon M

GeroScience

2024 Volume 46, Issue 3, Page(s) 3481–3501

Abstract: Cerebrovascular fragility and cerebral microhemorrhages (CMH) contribute to age-related cognitive impairment, mobility defects, and vascular cognitive impairment and dementia, impairing healthspan and reducing quality of life in the elderly. Insulin-like ...

Abstract	Cerebrovascular fragility and cerebral microhemorrhages (CMH) contribute to age-related cognitive impairment, mobility defects, and vascular cognitive impairment and dementia, impairing healthspan and reducing quality of life in the elderly. Insulin-like growth factor 1 (IGF-1) is a key vasoprotective growth factor that is reduced during aging. Circulating IGF-1 deficiency leads to the development of CMH and other signs of cerebrovascular dysfunction. Here our goal was to understand the contribution of IGF-1 signaling on vascular smooth muscle cells (VSMCs) to the development of CMH and associated gait defects. We used an inducible VSMC-specific promoter and an IGF-1 receptor (Igf1r) floxed mouse line (Myh11-Cre
MeSH term(s)	Aged ; Animals ; Humans ; Mice ; Gait ; Hypertension/genetics ; Hypertension/complications ; Insulin-Like Growth Factor I/metabolism ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/pathology ; Receptor, IGF Type 1/genetics ; Gait Disorders, Neurologic/genetics
Chemical Substances	Insulin-Like Growth Factor I (67763-96-6) ; Receptor, IGF Type 1 (EC 2.7.10.1) ; Igf1r protein, mouse
Language	English
Publishing date	2024-02-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-024-01090-7
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Article ; Online: Inflammatory markers are elevated in early pregnancy, but not late pregnancy, in women with overweight and obesity that later develop preeclampsia.

Jancsura, McKenzie K / Schmella, Mandy J / Helsabeck, Nathan / Gillespie, Shannon L / Roberts, James M / Conley, Yvette P / Hubel, Carl A

American journal of reproductive immunology (New York, N.Y. : 1989)

2023 Volume 90, Issue 3, Page(s) e13763

Abstract: Problem: Obesity and preeclampsia both involve a pathological inflammatory response, which may be how obesity increases preeclampsia risk. Previous studies have failed to assess robust measurements of inflammatory markers across gestation, specifically ... ...

Abstract	Problem: Obesity and preeclampsia both involve a pathological inflammatory response, which may be how obesity increases preeclampsia risk. Previous studies have failed to assess robust measurements of inflammatory markers across gestation, specifically in overweight/ obese women in the context of preeclampsia. Method of study: We measured 20 inflammatory markers in plasma via multiplex assay (ThermoFisher Inflammation 20 plex Human ProcartaPlex Panel) across the three trimesters of pregnancy in an existing cohort of overweight and obese women who developed preeclampsia (n = 37) and without preeclampsia (n = 74). Mann-Whitney U tests examined differences in inflammatory marker concentrations between cases and controls. Repeated measures ANOVA tests were used to explore differences in inflammatory marker concentrations over time within cases and controls. Results: Pro-inflammatory markers (IL-1α, IL-1β, IL-6, IFN-α, IFN-γ, GM-CSF, IL-12p70, IL-17α, TNF-α, IL-8) and anti-inflammatory markers (IL-4, IL-10, IL-13) were higher in the first and second trimester in participants who later developed preeclampsia compared to those who did not (p < .05). Only TNF-α and IL-8 remained elevated in the third trimester. Inflammatory markers did not change across pregnancy in preeclampsia cases but did increase across pregnancy in controls. Conclusion: Our findings diverge from prior studies, predominantly of non-obese women, that report lower circulating concentrations of anti-inflammatory cytokines in preeclampsia versus normotensive pregnancy, particularly by late pregnancy. We posit that women with overweight and obesity who develop preeclampsia entered pregnancy with a heightened pro-inflammatory state likely related to obesity, which increased risk for preeclampsia. Further studies are needed to investigate if inflammatory maker profiles differ between obese and non-obese women.
MeSH term(s)	Female ; Pregnancy ; Humans ; Overweight ; Pre-Eclampsia ; Interleukin-8 ; Tumor Necrosis Factor-alpha ; Obesity
Chemical Substances	Interleukin-8 ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2023-08-29
Publishing country	Denmark
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	604542-x
ISSN	1600-0897 ; 0271-7352 ; 8755-8920 ; 1046-7408
ISSN (online)	1600-0897
ISSN	0271-7352 ; 8755-8920 ; 1046-7408
DOI	10.1111/aji.13763
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Zs.A 1653: Show issues

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Article ; Online: Correction: Comparative study of PRPH2 D2 loop mutants reveals divergent disease mechanism in rods and cones.

Ikelle, Larissa / Makia, Mustafa / Lewis, Tylor / Crane, Ryan / Kakakhel, Mashal / Conley, Shannon M / Birtley, James R / Arshavsky, Vadim Y / Al-Ubaidi, Muayyad R / Naash, Muna I

Cellular and molecular life sciences : CMLS

2023 Volume 80, Issue 10, Page(s) 290

Language	English
Publishing date	2023-09-12
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-023-04929-y
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Article: Adherent but Not Suspension-Cultured Embryoid Bodies Develop into Laminated Retinal Organoids

Radojevic, Bojana / Conley, Shannon M. / Bennett, Lea D.

Journal of developmental biology. 2021 Sept. 10, v. 9, no. 3

2021

Abstract	Human induced pluripotent stem cells (iPSCs) are differentiated into three-dimensional (3D) retinal organoids to study retinogenesis and diseases that would otherwise be impossible. The complexity and low yield in current protocols remain a technical challenge, particularly for inexperienced personnel. Differentiation protocols require labor-intensive and time-consuming dissection of optic vesicles (OVs). Here we compare this method with a suspension method of developing retinal organoids. iPSCs were differentiated with standard protocols but the suspension-grown method omitted the re-plating of embryoid bodies and dissection of OVs. All other media and treatments were identical between developmental methods. Developmental maturation was evaluated with RT-qPCR and immunocytochemistry. Dissection- and suspension-derived retinal organoids displayed temporal biogenesis of retinal cell types. Differences in retinal organoids generated by the two methods of differentiation included temporal developmental and the organization of neural retina layers. Retinal organoids grown in suspension showed delayed development and disorganized retinal layers compared to the dissected retinal organoids. We found that omitting the re-plating of EBs to form OVs resulted in numerous OVs that were easy to identify and matured along a retinal lineage. While more efficient, the suspension method led to retinal organoids with disorganized retinal layers compared to those obtained using conventional dissection protocols.
Keywords	biogenesis ; dissection ; human resources ; humans ; immunocytochemistry ; organoids ; retina
Language	English
Dates of publication	2021-0910
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2720870-9
ISSN	2221-3759
ISSN	2221-3759
DOI	10.3390/jdb9030038
Database	NAL-Catalogue (AGRICOLA)

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Article: Convergent, discriminant, and known groups validity of the Behavioral Assessment Screening Tool (BAST) in chronic traumatic brain injury.

Juengst, Shannon B / Wright, Brittany / Vos, Leia / Rodriguez, Gabriel / Conley, Michael / Terhorst, Lauren

Research square

2024

Abstract: The Behavioral Assessment Screening Tool (BAST) measures self-reported neurobehavioral symptoms commonly experienced by adults with traumatic brain injury (TBI). To assess the convergent, discriminant, and known-groups validity of the BAST among ... ...

Abstract	The Behavioral Assessment Screening Tool (BAST) measures self-reported neurobehavioral symptoms commonly experienced by adults with traumatic brain injury (TBI). To assess the convergent, discriminant, and known-groups validity of the BAST among community-dwelling adults with chronic traumatic brain injury (TBI), we conducted correlation analyses and tests of group differences with previously validated symptom measures in two samples (n = 111, n = 134). Measures used for comparison were: Patient Health Questionnaire (depression), Generalized Anxiety Disorder-7 (anxiety), Positive and Negative Affect Schedule, Frontal Systems Behavior Scale (Executive Dysfunction, Apathy, Disinhibition), Modified Fatigue Impact Scale, PROMIS Fatigue, Aggression Questionnaire (anger, hostility, physical and verbal aggression), and Alcohol Use Disorders Test (alcohol misuse). BAST subscales had stronger correlations with measures of similar (\|r\|=.602-.828, p < .001) and related (\|r\|>.30, p < .001) constructs and weaker correlations (\|r\|<.300) with measures of dissimilar/unrelated constructs, supporting hypotheses of convergent and discriminant validity, respectively. Statistically significant group differences (p's < .001) in BAST subscales were found, with large effect sizes (Cohen's d = 1.2-1.9), for known-groups with moderate-severe depression, moderate-severe anxiety, clinically significant fatigue, problematic disinhibited and frontal-executive behaviors, and alcohol use. Conclusions: Results support the convergent and discriminant validity of the BAST subscales. The BAST was specifically developed as a self-reported measure for remote symptom reporting, supporting its incorporation into mobile health platforms to improve chronic symptom monitoring in community-dwelling adults with TBI. With further validation research, the BAST could be used for early identification of persons with TBI who could benefit from intervention.
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3909294/v1
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Article: Gene Therapy to the Retina and the Cochlea.

Crane, Ryan / Conley, Shannon M / Al-Ubaidi, Muayyad R / Naash, Muna I

Frontiers in neuroscience

2021 Volume 15, Page(s) 652215

Abstract: Vision and hearing disorders comprise the most common sensory disorders found in people. Many forms of vision and hearing loss are inherited and current treatments only provide patients with temporary or partial relief. As a result, developing genetic ... ...

Abstract	Vision and hearing disorders comprise the most common sensory disorders found in people. Many forms of vision and hearing loss are inherited and current treatments only provide patients with temporary or partial relief. As a result, developing genetic therapies for any of the several hundred known causative genes underlying inherited retinal and cochlear disorders has been of great interest. Recent exciting advances in gene therapy have shown promise for the clinical treatment of inherited retinal diseases, and while clinical gene therapies for cochlear disease are not yet available, research in the last several years has resulted in significant advancement in preclinical development for gene delivery to the cochlea. Furthermore, the development of somatic targeted genome editing using CRISPR/Cas9 has brought new possibilities for the treatment of dominant or gain-of-function disease. Here we discuss the current state of gene therapy for inherited diseases of the retina and cochlea with an eye toward areas that still need additional development.
Language	English
Publishing date	2021-03-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2021.652215
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