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Article ; Online: Brown adipocytes from induced pluripotent stem cells-how far have we come?

Brown, Aaron C

Annals of the New York Academy of Sciences

2019 Volume 1463, Issue 1, Page(s) 9–22

Abstract: A global increase in the number of individuals who are either overweight or obese is leading to a higher incidence of type 2 diabetes (T2D). Behavioral interventions for the treatment of obesity have yet to deliver desired outcomes, thus introducing a ... ...

Abstract	A global increase in the number of individuals who are either overweight or obese is leading to a higher incidence of type 2 diabetes (T2D). Behavioral interventions for the treatment of obesity have yet to deliver desired outcomes, thus introducing a pressing need for molecular- and cellular-based therapies. Excess energy from food is stored in the form of triglycerides in white adipose tissue, which expands during weight gain and can lead to insulin resistance and T2D. By contrast, brown adipose tissue (BAT) releases energy from metabolic substrates in the form of heat and secretes factors that can reverse metabolic disease by acting systemically. Therefore, the ability to increase BAT activity is a promising approach to improve energy balance and metabolic homeostasis. Methods are now being developed to generate brown adipocytes from human induced pluripotent stem cells (hiPSCs), which would (1) provide an unlimited source of cellular material to study human brown adipogenesis, and (2) could be used to develop drug- and cell-based therapies for the treatment of metabolic complications associated with obesity. This article reviews basic BAT biology and details the current progress toward developing brown adipocytes from hiPSCs.
MeSH term(s)	Adipocytes, Brown/physiology ; Adipogenesis/physiology ; Adipose Tissue, Brown/cytology ; Adipose Tissue, Brown/physiology ; Animals ; Cell Differentiation/physiology ; Cells, Cultured ; Humans ; Induced Pluripotent Stem Cells/physiology ; Induced Pluripotent Stem Cells/transplantation
Language	English
Publishing date	2019-10-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	211003-9
ISSN	1749-6632 ; 0077-8923
ISSN (online)	1749-6632
ISSN	0077-8923
DOI	10.1111/nyas.14257
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Article ; Online: Long-Term Culture of Nephron Progenitor Cells Ex Vivo.

Brown, Aaron C / Gupta, Ashwani K / Oxburgh, Leif

Methods in molecular biology (Clifton, N.J.)

2019 Volume 1926, Page(s) 63–75

Abstract: Nephrons differentiate from the cap mesenchyme of the fetal kidney. Nephron progenitor cells that populate the cap mesenchyme efficiently balance self-renewal and epithelial differentiation to enable repeated rounds of nephron formation during ... ...

Abstract	Nephrons differentiate from the cap mesenchyme of the fetal kidney. Nephron progenitor cells that populate the cap mesenchyme efficiently balance self-renewal and epithelial differentiation to enable repeated rounds of nephron formation during development. Here we describe a method to isolate and propagate these cells from the embryonic mouse kidney. Using this method, nephron progenitor cells from a single litter of mice can be propagated to hundreds of millions of cells that express appropriate markers of the undifferentiated state and retain epithelial differentiation capacity in vitro.
MeSH term(s)	Animals ; Cell Differentiation/physiology ; Cells, Cultured ; Humans ; Kidney/cytology ; Mice ; Organogenesis/genetics ; Organogenesis/physiology ; Stem Cells/cytology
Language	English
Publishing date	2019-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9021-4_6
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Article ; Online: The physics of knocking over LEGO minifigures with time reversal focused vibrations for use in a museum exhibit.

Barnes, Lucas A / Anderson, Brian E / Le Bas, Pierre-Yves / Kingsley, Adam D / Brown, Aaron C / Thomsen, Henrik R

The Journal of the Acoustical Society of America

2022 Volume 151, Issue 2, Page(s) 738

Abstract: Time reversal (TR) is a method of focusing wave energy at a point in space. The optimization of a TR demonstration is described, which knocks over one selected LEGO minifigure among other minifigures by focusing the vibrations within an aluminum plate at ...

Abstract	Time reversal (TR) is a method of focusing wave energy at a point in space. The optimization of a TR demonstration is described, which knocks over one selected LEGO minifigure among other minifigures by focusing the vibrations within an aluminum plate at the target minifigure. The aim is to achieve a high repeatability of the demonstration along with reduced costs to create a museum exhibit. By comparing the minifigure's motion to the plate's motion directly beneath its feet, it is determined that a major factor inhibiting the repeatability is that the smaller vibrations before the focal event cause the minifigure to bounce repeatedly and it ends up being in the air during the main vibrational focal event, which was intended to launch the minifigure. The deconvolution TR technique is determined to be optimal in providing the demonstration repeatability. The amplitude, frequency, and plate thickness are optimized in a laboratory setting. An eddy current sensor is then used to reduce the costs, and the impact on the repeatability is determined. A description is given of the implementation of the demonstration for a museum exhibit. This demonstration illustrates the power of the focusing acoustic waves, and the principles learned by optimizing this demonstration can be applied to other real-world applications.
Language	English
Publishing date	2022-03-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	219231-7
ISSN	1520-8524 ; 0001-4966
ISSN (online)	1520-8524
ISSN	0001-4966
DOI	10.1121/10.0009364
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Article ; Online: Correction: Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells.

Martino, Julieta / Siri, Sebastián Omar / Calzetta, Nicolás Luis / Paviolo, Natalia Soledad / Garro, Cintia / Pansa, Maria F / Carbajosa, Sofía / Brown, Aaron C / Bocco, José Luis / Gloger, Israel / Drewes, Gerard / Madauss, Kevin P / Soria, Gastón / Gottifredi, Vanesa

eLife

2023 Volume 12

Language	English
Publishing date	2023-11-14
Publishing country	England
Document type	Published Erratum
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.94414
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Article ; Online: Optogenetic activation of UCP1-dependent thermogenesis in brown adipocytes.

Doucette, Chad C / Nguyen, Daniel C / Barteselli, Davide / Blanchard, Sophia / Pelletier, Mason / Kesharwani, Devesh / Jachimowicz, Ed / Su, Su / Karolak, Michele / Brown, Aaron C

iScience

2023 Volume 26, Issue 4, Page(s) 106560

Abstract: Brown adipocytes are unique in that they expend energy and produce heat to maintain euthermia through expression of uncoupling protein-1 (UCP1). Given their propensity to stimulate weight loss and promote resistance to obesity, they are a compelling ... ...

Abstract	Brown adipocytes are unique in that they expend energy and produce heat to maintain euthermia through expression of uncoupling protein-1 (UCP1). Given their propensity to stimulate weight loss and promote resistance to obesity, they are a compelling interventional target for obesity-related disorders. Here, we tested whether an optogenetic approach could be used to activate UCP1-dependent thermogenesis in brown adipocytes. We generated brown adipocytes expressing a bacterial-derived photoactivatable adenylyl cyclase (bPAC) that, upon blue light stimulation, increases UCP1 expression, fuel uptake and thermogenesis. This unique system allows for precise, chemical free, temporal control of UCP1-dependent thermogenesis, which can aid in our understanding of brown adipocyte biology and development of therapies that target obesity-related disorders.
Language	English
Publishing date	2023-04-01
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.106560
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Article ; Online: Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells.

eLife

2023 Volume 12

Abstract: The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute DNA replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, DNA damage is accepted as a prerequisite for SL in BRCA2- ... ...

Abstract	The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute DNA replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, DNA damage is accepted as a prerequisite for SL in BRCA2-deficient cells. In contrast, here we show that inhibiting ROCK in BRCA2-deficient cells triggers SL independently from acute replication stress. Such SL is preceded by polyploidy and binucleation resulting from cytokinesis failure. Such initial mitosis abnormalities are followed by other M phase defects, including anaphase bridges and abnormal mitotic figures associated with multipolar spindles, supernumerary centrosomes and multinucleation. SL was also triggered by inhibiting Citron Rho-interacting kinase, another enzyme that, similarly to ROCK, regulates cytokinesis. Together, these observations demonstrate that cytokinesis failure triggers mitotic abnormalities and SL in BRCA2-deficient cells. Furthermore, the prevention of mitotic entry by depletion of Early mitotic inhibitor 1 (EMI1) augmented the survival of BRCA2-deficient cells treated with ROCK inhibitors, thus reinforcing the association between M phase and cell death in BRCA2-deficient cells. This novel SL differs from the one triggered by PARPi and uncovers mitosis as an Achilles heel of BRCA2-deficient cells.
MeSH term(s)	Anaphase ; DNA Damage ; Mitosis ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Synthetic Lethal Mutations ; rho-Associated Kinases/antagonists & inhibitors ; BRCA2 Protein/genetics ; Humans
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; rho-Associated Kinases (EC 2.7.11.1) ; BRCA2 Protein
Language	English
Publishing date	2023-04-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.80254
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Article: Unraveling quad fever: Severe hyperthermia after traumatic cervical spinal cord injury.

Watson, Carlton C L / Shaikh, Dooniya / DiGiacomo, Jody C / Brown, Aaron C / Wallace, Raina / Singh, Shridevi / Szydziaka, Lisa / Cardozo-Stolberg, Sara / Angus, L D George

Chinese journal of traumatology = Zhonghua chuang shang za zhi

2022 Volume 26, Issue 1, Page(s) 27–32

Abstract: Purpose: There are many infectious and inflammatory causes for elevated core-body temperatures, though they rarely pass 40 ℃ (104 ℉). The term "quad fever" is used for extreme hyperpyrexia in the setting of acute cervical spinal cord injuries (SCIs). ... ...

Abstract	Purpose: There are many infectious and inflammatory causes for elevated core-body temperatures, though they rarely pass 40 ℃ (104 ℉). The term "quad fever" is used for extreme hyperpyrexia in the setting of acute cervical spinal cord injuries (SCIs). The traditional methods of treating hyperpyrexia are often ineffective and reported morbidity and mortality rates approach 100%. This study aims to identify the incidence of elevated temperatures in SCIs at our institution and assess the effectiveness of using a non-invasive dry water temperature management system as a treatment modality with mortality. Methods: A retrospective analysis of acute SCI patients requiring surgical intensive care unit admission who experienced fevers ≥ 40 ℃ (104 ℉) were compared to patients with maximum temperatures < 40 ℃. Patients ≥18 years old who sustained an acute traumatic SCI were included in this study. Patients who expired in the emergency department; had a SCI without radiologic abnormality; had neuropraxia; were admitted to any location other than the surgical intensive care unit; or had positive blood cultures were excluded. SAS 9.4 was used to conduct statistical analysis. Results: Over the 9-year study period, 35 patients were admitted to the surgical intensive care unit with a verified SCI. Seven patients experienced maximum temperatures of ≥ 40 ℃. Six of those patients were treated with the dry water temperature management system with an overall mortality of 57.1% in this subgroup. The mortality rate for the 28 patients who experienced a maximum temperature of ≤ 40 ℃ was 21.4% (p = 0.16). Conclusion: The diagnosis of quad fever should be considered in patients with cervical SCI in the presence of hyperthermia. In this study, there was no significant difference in mortality between quad fever patients treated with a dry water temperature management system versus SCI patients without quad fever. The early use of a dry water temperature management system appears to decrease the mortality rate of quad fever.
MeSH term(s)	Humans ; Adolescent ; Hyperthermia ; Retrospective Studies ; Cervical Cord ; Spinal Cord Injuries/complications ; Spinal Cord Injuries/surgery ; Neck Injuries ; Soft Tissue Injuries ; Hyperthermia, Induced
Language	English
Publishing date	2022-01-21
Publishing country	China
Document type	Journal Article
ZDB-ID	2276839-7
ISSN	1008-1275
ISSN	1008-1275
DOI	10.1016/j.cjtee.2022.01.006
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Article ; Online: A synthetic niche for nephron progenitor cells.

Brown, Aaron C / Muthukrishnan, Sree Deepthi / Oxburgh, Leif

Developmental cell

2015 Volume 34, Issue 2, Page(s) 229–241

Abstract: FGF, BMP, and WNT balance embryonic nephron progenitor cell (NPC) renewal and differentiation. By modulating these pathways, we have created an in vitro niche in which NPCs from embryonic kidneys or derived from human embryonic stem cells can be ... ...

Abstract	FGF, BMP, and WNT balance embryonic nephron progenitor cell (NPC) renewal and differentiation. By modulating these pathways, we have created an in vitro niche in which NPCs from embryonic kidneys or derived from human embryonic stem cells can be propagated. NPC cultures expanded up to one billion-fold in this environment can be induced to form tubules expressing nephron differentiation markers. Single-cell culture reveals phenotypic variability within the early CITED1-expressing NPC compartment, indicating that it is a mixture of cells with varying progenitor potential. Furthermore, we find that the developmental age of NPCs does not correlate with propagation capacity, indicating that cessation of nephrogenesis is related to factors other than an intrinsic clock. This in vitro nephron progenitor niche will have important applications for expansion of cells for engraftment and will facilitate investigation of mechanisms that determine the balance between renewal and differentiation in these cells.
MeSH term(s)	Animals ; Bone Morphogenetic Proteins/metabolism ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Embryonic Stem Cells/cytology ; Enzyme Activation ; Fibroblast Growth Factors/metabolism ; Homeodomain Proteins/biosynthesis ; Homeodomain Proteins/genetics ; Mice ; Mice, Inbred ICR ; Mice, Transgenic ; Nephrons/cytology ; Nephrons/embryology ; Nuclear Proteins/biosynthesis ; Nuclear Proteins/genetics ; Organogenesis ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; Smad1 Protein/antagonists & inhibitors ; Smad1 Protein/metabolism ; Smad5 Protein/antagonists & inhibitors ; Smad5 Protein/metabolism ; Trans-Activators/biosynthesis ; Trans-Activators/genetics ; Transcription Factors/biosynthesis ; Transcription Factors/genetics ; Wnt Proteins/metabolism
Chemical Substances	Bone Morphogenetic Proteins ; Cited1 protein, mouse ; Homeodomain Proteins ; LDN 193189 ; Nuclear Proteins ; Pyrazoles ; Pyrimidines ; Six2 protein, mouse ; Smad1 Protein ; Smad1 protein, mouse ; Smad5 Protein ; Smad5 protein, mouse ; Trans-Activators ; Transcription Factors ; Wnt Proteins ; Fibroblast Growth Factors (62031-54-3)
Language	English
Publishing date	2015-07-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2054967-2
ISSN	1878-1551 ; 1534-5807
ISSN (online)	1878-1551
ISSN	1534-5807
DOI	10.1016/j.devcel.2015.06.021
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Article ; Online: Bone morphogenetic protein signaling in nephron progenitor cells.

Oxburgh, Leif / Brown, Aaron C / Muthukrishnan, Sree Deepthi / Fetting, Jennifer L

Pediatric nephrology (Berlin, Germany)

2013 Volume 29, Issue 4, Page(s) 531–536

Abstract: Bone morphogenetic protein (BMP) signaling plays an essential role in many aspects of kidney development, and is a major determinant of outcome in kidney injury. BMP treatment is also an essential component of protocols for differentiation of nephron ... ...

Abstract	Bone morphogenetic protein (BMP) signaling plays an essential role in many aspects of kidney development, and is a major determinant of outcome in kidney injury. BMP treatment is also an essential component of protocols for differentiation of nephron progenitors from pluripotent stem cells. This review discusses the role of BMP signaling to nephron progenitor cells in each of these contexts.
MeSH term(s)	Animals ; Bone Morphogenetic Proteins/metabolism ; Humans ; Nephrons/embryology ; Nephrons/metabolism ; Organogenesis/physiology ; Signal Transduction/physiology ; Stem Cells/metabolism
Chemical Substances	Bone Morphogenetic Proteins
Language	English
Publishing date	2013-08-20
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	631932-4
ISSN	1432-198X ; 0931-041X
ISSN (online)	1432-198X
ISSN	0931-041X
DOI	10.1007/s00467-013-2589-2
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Article ; Online: BMP signaling in the nephron progenitor niche.

Oxburgh, Leif / Brown, Aaron C / Fetting, Jennifer / Hill, Beth

Pediatric nephrology (Berlin, Germany)

2011 Volume 26, Issue 9, Page(s) 1491–1497

Abstract: Bone morphogenic proteins (BMPs) play diverse roles in embryonic kidney development, regulating essential aspects of both ureteric bud and nephron development. In this review, we provide an overview of reported expression patterns and functions of BMP ... ...

Abstract	Bone morphogenic proteins (BMPs) play diverse roles in embryonic kidney development, regulating essential aspects of both ureteric bud and nephron development. In this review, we provide an overview of reported expression patterns and functions of BMP signaling components within the nephrogenic zone or nephron progenitor niche of the developing kidney. Reported in situ hybridization results are relatively challenging to interpret and sometimes conflicting. Comparing these with high-resolution microarray gene expression data available in Gudmap, we propose a consensus gene expression pattern indicating that essential components of both the Smad-mediated pathway and the Smad-independent MAPK pathways are expressed in the nephron progenitor cell compartment and may be activated by BMPs, but that cortical interstitium may only be able to respond to BMPs through mitogen activated protein kinase (MAPK) signaling. Localization of phosphorylated Smad transcription factors and studies of a BMP reporter mouse strain however indicate limited transcriptional responsiveness to Smad-mediated signaling in cap mesenchyme. An overview of genetic inactivation, organ culture, and primary cell studies indicates that BMP signaling may elicit two important biological outcomes in the nephrogenic zone: survival of the cap mesenchyme, and the physical segregation of interstitial and progenitor cell compartments. Ongoing studies using a novel primary cell system that establishes the nephrogenic zone ex vivo are pursuing the concept that the balance between Smad-mediated and Smad-independent responses to BMP ligand may underlie these distinct outcomes.
MeSH term(s)	Animals ; Bone Morphogenetic Proteins/genetics ; Bone Morphogenetic Proteins/metabolism ; Gene Expression Regulation, Developmental ; Humans ; Nephrons/embryology ; Nephrons/metabolism ; Signal Transduction/genetics ; Stem Cell Niche/genetics ; Stem Cells/metabolism
Chemical Substances	Bone Morphogenetic Proteins
Language	English
Publishing date	2011-03-04
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	631932-4
ISSN	1432-198X ; 0931-041X
ISSN (online)	1432-198X
ISSN	0931-041X
DOI	10.1007/s00467-011-1819-8
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