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Article ; Online: Engineering a CRISPRoff Platform to Modulate Expression of Myeloid Cell Leukemia (MCL-1) in Committed Oligodendrocyte Neural Precursor Cells.

Gil, Melanie / Hamann, Catherine A / Brunger, Jonathan M / Gama, Vivian

2024 Volume 14, Issue 1, Page(s) e4913

Abstract: In vitro differentiation of human pluripotent stem cell (hPSC) model systems has furthered our understanding of human development. Techniques used to elucidate gene function during early development have encountered technical challenges, especially when ... ...

Abstract	In vitro differentiation of human pluripotent stem cell (hPSC) model systems has furthered our understanding of human development. Techniques used to elucidate gene function during early development have encountered technical challenges, especially when targeting embryonic lethal genes. The introduction of CRISPRoff by Nuñez and collaborators provides an opportunity to heritably silence genes during long-term differentiation. We modified CRISPRoff and sgRNA Sleeping Beauty transposon vectors that depend on tetracycline-controlled transcriptional activation to silence the expression of embryonic lethal genes at different stages of differentiation in a stable manner. We provide instructions on how to generate sgRNA transposon vectors that can be used in combination with our CRISPRoff transposon vector and a stable hPSC line. We validate the use of this tool by silencing MCL-1, an anti-apoptotic protein, which results in pre-implantation embryonic lethality in mice; this protein is necessary for oligodendrocyte and hematopoietic stem cell development and is required for the in vitro survival of hPSCs. In this protocol, we use an adapted version of the differentiation protocol published by Douvaras and Fossati (2015) to generate oligodendrocyte lineage cells from human embryonic stem cells (hESCs). After introduction of the CRISPRoff and sgRNAs transposon vectors in hESCs, we silence
Language	English
Publishing date	2024-01-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.4913
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Engineering approaches for RNA-based and cell-based osteoarthritis therapies.

DeJulius, Carlisle R / Walton, Bonnie L / Colazo, Juan M / d'Arcy, Richard / Francini, Nora / Brunger, Jonathan M / Duvall, Craig L

Nature reviews. Rheumatology

2024 Volume 20, Issue 2, Page(s) 81–100

Abstract: Osteoarthritis (OA) is a chronic, debilitating disease that substantially impairs the quality of life of affected individuals. The underlying mechanisms of OA are diverse and are becoming increasingly understood at the systemic, tissue, cellular and gene ...

Abstract	Osteoarthritis (OA) is a chronic, debilitating disease that substantially impairs the quality of life of affected individuals. The underlying mechanisms of OA are diverse and are becoming increasingly understood at the systemic, tissue, cellular and gene levels. However, the pharmacological therapies available remain limited, owing to drug delivery barriers, and consist mainly of broadly immunosuppressive regimens, such as corticosteroids, that provide only short-term palliative benefits and do not alter disease progression. Engineered RNA-based and cell-based therapies developed with synthetic chemistry and biology tools provide promise for future OA treatments with durable, efficacious mechanisms of action that can specifically target the underlying drivers of pathology. This Review highlights emerging classes of RNA-based technologies that hold potential for OA therapies, including small interfering RNA for gene silencing, microRNA and anti-microRNA for multi-gene regulation, mRNA for gene supplementation, and RNA-guided gene-editing platforms such as CRISPR-Cas9. Various cell-engineering strategies are also examined that potentiate disease-dependent, spatiotemporally regulated production of therapeutic molecules, and a conceptual framework is presented for their application as OA treatments. In summary, this Review highlights modern genetic medicines that have been clinically approved for other diseases, in addition to emerging genome and cellular engineering approaches, with the goal of emphasizing their potential as transformative OA treatments.
MeSH term(s)	Humans ; CRISPR-Cas Systems ; RNA ; Quality of Life ; Gene Editing ; Osteoarthritis/genetics ; Osteoarthritis/therapy
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2024-01-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2491532-4
ISSN	1759-4804 ; 1759-4790
ISSN (online)	1759-4804
ISSN	1759-4790
DOI	10.1038/s41584-023-01067-4
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Article ; Online: Nuclear receptor ligand screening in an iPSC-derived in vitro blood-brain barrier model identifies new contributors to leptin transport.

Shi, Yajuan / Kim, Hyosung / Hamann, Catherine A / Rhea, Elizabeth M / Brunger, Jonathan M / Lippmann, Ethan S

Fluids and barriers of the CNS

2022 Volume 19, Issue 1, Page(s) 77

Abstract: Background: The hormone leptin exerts its function in the brain to reduce food intake and increase energy expenditure to prevent obesity. However, most obese subjects reflect the resistance to leptin even with elevated serum leptin. Considering that ... ...

Abstract	Background: The hormone leptin exerts its function in the brain to reduce food intake and increase energy expenditure to prevent obesity. However, most obese subjects reflect the resistance to leptin even with elevated serum leptin. Considering that leptin must cross the blood-brain barrier (BBB) in several regions to enter the brain parenchyma, altered leptin transport through the BBB might play an important role in leptin resistance and other biological conditions. Here, we report the use of a human induced pluripotent stem cell (iPSC)-derived BBB model to explore mechanisms that influence leptin transport. Methods: iPSCs were differentiated into brain microvascular endothelial cell (BMEC)-like cells using standard methods. BMEC-like cells were cultured in Transwell filters, treated with ligands from a nuclear receptor agonist library, and assayed for leptin transport using an enzyme-linked immune sorbent assay. RNA sequencing was further used to identify differentially regulated genes and pathways. The role of a select hit in leptin transport was tested with the competitive substrate assay and after gene knockdown using CRISPR techniques. Results: Following a screen of 73 compounds, 17β-estradiol was identified as a compound that could significantly increase leptin transport. RNA sequencing revealed many differentially expressed transmembrane transporters after 17β-estradiol treatment. Of these, cationic amino acid transporter-1 (CAT-1, encoded by SLC7A1) was selected for follow-up analyses due to its high and selective expression in BMECs in vivo. Treatment of BMEC-like cells with CAT-1 substrates, as well as knockdown of CAT-1 expression via CRISPR-mediated epigenome editing, yielded significant increases in leptin transport. Conclusions: A major female sex hormone, as well as an amino acid transporter, were revealed as regulators of leptin BBB transport in the iPSC-derived BBB model. Outcomes from this work provide insights into regulation of hormone transport across the BBB.
MeSH term(s)	Amino Acid Transport Systems, Basic/metabolism ; Blood-Brain Barrier/metabolism ; Cells, Cultured ; Estradiol/metabolism ; Estradiol/pharmacology ; Female ; Humans ; Induced Pluripotent Stem Cells/physiology ; Leptin/metabolism ; Leptin/pharmacology ; Ligands ; Receptors, Cytoplasmic and Nuclear/metabolism ; Receptors, Cytoplasmic and Nuclear/pharmacology
Chemical Substances	Amino Acid Transport Systems, Basic ; Leptin ; Ligands ; Receptors, Cytoplasmic and Nuclear ; Estradiol (4TI98Z838E)
Language	English
Publishing date	2022-09-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2595406-4
ISSN	2045-8118 ; 2045-8118
ISSN (online)	2045-8118
ISSN	2045-8118
DOI	10.1186/s12987-022-00375-3
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Article ; Online: Instructional materials that control cellular activity through synthetic Notch receptors.

Lee, Joanne C / Brien, Hannah J / Walton, Bonnie L / Eidman, Zachary M / Toda, Satoshi / Lim, Wendell A / Brunger, Jonathan M

Biomaterials

2023 Volume 297, Page(s) 122099

Abstract: The field of regenerative engineering relies primarily on the dual technical platforms of cell selection/conditioning and biomaterial fabrication to support directed cell differentiation. As the field has matured, an appreciation for the influence of ... ...

Abstract	The field of regenerative engineering relies primarily on the dual technical platforms of cell selection/conditioning and biomaterial fabrication to support directed cell differentiation. As the field has matured, an appreciation for the influence of biomaterials on cell behaviors has resulted in engineered matrices that meet biomechanical and biochemical demands of target pathologies. Yet, despite advances in methods to produce designer matrices, regenerative engineers remain unable to reliably orchestrate behaviors of therapeutic cells in situ. Here, we present a platform named MATRIX whereby cellular responses to biomaterials can be custom defined by combining engineered materials with cells expressing cognate synthetic biology control modules. Such privileged channels of material-to-cell communication can activate synthetic Notch receptors and govern activities as diverse as transcriptome engineering, inflammation attenuation, and pluripotent stem cell differentiation, all in response to materials decorated with otherwise bioinert ligands. Further, we show that engineered cellular behaviors are confined to programmed biomaterial surfaces, highlighting the potential to use this platform to spatially organize cellular responses to bulk, soluble factors. This integrated approach of co-engineering cells and biomaterials for orthogonal interactions opens new avenues for reproducible control of cell-based therapies and tissue replacements.
MeSH term(s)	Receptors, Artificial ; Receptors, Notch ; Biocompatible Materials ; Cell Differentiation ; Pluripotent Stem Cells ; Tissue Engineering/methods
Chemical Substances	Receptors, Artificial ; Receptors, Notch ; Biocompatible Materials
Language	English
Publishing date	2023-03-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2023.122099
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Article: A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine.

Walton, Bonnie L / Shattuck-Brandt, Rebecca / Hamann, Catherine A / Tung, Victoria W / Colazo, Juan M / Brand, David D / Hasty, Karen A / Duvall, Craig L / Brunger, Jonathan M

bioRxiv : the preprint server for biology

2024

Abstract: Objective: Investigational cell therapies have been developed as disease-modifying agents for the treatment of osteoarthritis (OA), including those that inducibly respond to inflammatory factors driving OA progression. However, dysregulated inflammatory ...

Abstract	Objective: Investigational cell therapies have been developed as disease-modifying agents for the treatment of osteoarthritis (OA), including those that inducibly respond to inflammatory factors driving OA progression. However, dysregulated inflammatory cascades do not specifically signify the presence of OA. Here, we deploy a synthetic receptor platform that regulates cell behaviors in an arthritis-specific fashion to confine transgene expression to sites characterized by cartilage degeneration. Methods: An scFv specific for type II collagen (CII) was used to produce a synthetic Notch (synNotch) receptor that enables "CII-synNotch" mesenchymal stromal cells (MSCs) to recognize CII fibers exposed in damaged cartilage. Engineered cell activation by both CII-treated culture surfaces and on primary tissue samples was measured via inducible reporter transgene expression. TGFβ3-expressing cells were assessed for cartilage anabolic gene expression via qRT-PCR. In a co-culture with CII-synNotch MSCs engineered to express IL-1Ra, ATDC5 chondrocytes were stimulated with IL-1α, and inflammatory responses of ATDC5s were profiled via qRT-PCR and an NF-κB reporter assay. Results: CII-synNotch MSCs are highly responsive to CII, displaying activation ranges over 40-fold in response to physiologic CII inputs. CII-synNotch cells exhibit the capacity to distinguish between healthy and damaged cartilage tissue and constrain transgene expression to regions of exposed CII fibers. Receptor-regulated TGFβ3 expression resulted in upregulation of Conclusion: This work demonstrates proof-of-concept that the synNotch platform guides MSCs for spatially regulated, disease-dependent delivery of OA-relevant biologic drugs.
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.31.578281
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Article ; Online: A Synthetic Gene Circuit for Self-Regulating Delivery of Biologic Drugs in Engineered Tissues.

Pferdehirt, Lara / Ross, Alison K / Brunger, Jonathan M / Guilak, Farshid

Tissue engineering. Part A

2019 Volume 25, Issue 9-10, Page(s) 809–820

Abstract: Impact statement: We engineered a synthetic transcription system based on nuclear factor kappa-light-chain-enhancer of activated B cells signaling that can attenuate the effects of the inflammatory cytokine interleukin (IL)-1α in a self-regulating ... ...

Abstract	Impact statement: We engineered a synthetic transcription system based on nuclear factor kappa-light-chain-enhancer of activated B cells signaling that can attenuate the effects of the inflammatory cytokine interleukin (IL)-1α in a self-regulating manner. This system responds in a time- and dose-dependent manner to rapidly produce therapeutic levels of IL-1 receptor antagonist (IL-1Ra). The use of lentiviral gene therapy allows this system to be utilized through different transduction methods and in different cell types for a variety of applications. Broadly, this approach may be applicable in developing autoregulated biologic systems for tissue engineering and drug delivery in a range of disease applications.
MeSH term(s)	Animals ; Biological Products/metabolism ; Gene Regulatory Networks ; Genes, Synthetic ; Genetic Therapy ; HEK293 Cells ; Humans ; Interleukin 1 Receptor Antagonist Protein/biosynthesis ; Interleukin 1 Receptor Antagonist Protein/genetics ; Interleukin-1alpha/biosynthesis ; Interleukin-1alpha/genetics ; Mice ; Tissue Engineering
Chemical Substances	Biological Products ; IL1A protein, human ; IL1RN protein, human ; Interleukin 1 Receptor Antagonist Protein ; Interleukin-1alpha
Language	English
Publishing date	2019-05-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2420582-5
ISSN	1937-335X ; 1937-3341
ISSN (online)	1937-335X
ISSN	1937-3341
DOI	10.1089/ten.TEA.2019.0027
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Article ; Online: Nonviral

ACS nano

2023 Volume 17, Issue 17, Page(s) 16412–16431

Abstract: The complexity of CRISPR machinery is a challenge to its application for ... ...

Abstract	The complexity of CRISPR machinery is a challenge to its application for nonviral
MeSH term(s)	Mice ; Animals ; CRISPR-Cas Systems/genetics ; Silicon ; Porosity ; Polymers ; Nanoparticles
Chemical Substances	Silicon (Z4152N8IUI) ; Polymers
Language	English
Publishing date	2023-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1936-086X
ISSN (online)	1936-086X
DOI	10.1021/acsnano.2c12261
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Article ; Online: Long non-coding RNA

Huynh, Nguyen Pt / Gloss, Catherine C / Lorentz, Jeremiah / Tang, Ruhang / Brunger, Jonathan M / McAlinden, Audrey / Zhang, Bo / Guilak, Farshid

eLife

2020 Volume 9

Abstract: The roles of long noncoding RNAs (lncRNAs) in musculoskeletal development, disease, and regeneration remain poorly understood. Here, we identified the novel ... ...

Abstract	The roles of long noncoding RNAs (lncRNAs) in musculoskeletal development, disease, and regeneration remain poorly understood. Here, we identified the novel lncRNA
MeSH term(s)	Binding Sites ; Cell Differentiation/genetics ; Cells, Cultured ; Chondrocytes/cytology ; Chondrogenesis/genetics ; Extracellular Matrix/metabolism ; Gene Editing ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks ; Humans ; Immunohistochemistry ; Interferon-gamma/metabolism ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Protein Binding ; RNA, Long Noncoding/genetics ; Signal Transduction
Chemical Substances	RNA, Long Noncoding ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2020-03-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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.49558
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Article ; Online: A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery.

Choi, Yun-Rak / Collins, Kelsey H / Springer, Luke E / Pferdehirt, Lara / Ross, Alison K / Wu, Chia-Lung / Moutos, Franklin T / Harasymowicz, Natalia S / Brunger, Jonathan M / Pham, Christine T N / Guilak, Farshid

Science advances

2021 Volume 7, Issue 36, Page(s) eabj1414

Abstract: Biologic drug therapies are increasingly used for inflammatory diseases such as rheumatoid arthritis but may cause significant adverse effects when delivered continuously at high doses. We used CRISPR-Cas9 genome editing of iPSCs to create a synthetic ... ...

Abstract	Biologic drug therapies are increasingly used for inflammatory diseases such as rheumatoid arthritis but may cause significant adverse effects when delivered continuously at high doses. We used CRISPR-Cas9 genome editing of iPSCs to create a synthetic gene circuit that senses changing levels of endogenous inflammatory cytokines to trigger a proportional therapeutic response. Cells were engineered into cartilaginous constructs that showed rapid activation and recovery in response to inflammation in vitro or in vivo. In the murine K/BxN model of inflammatory arthritis, bioengineered implants significantly mitigated disease severity as measured by joint pain, structural damage, and systemic and local inflammation. Therapeutic implants completely prevented increased pain sensitivity and bone erosions, a feat not achievable by current clinically available disease-modifying drugs. Combination tissue engineering and synthetic biology promises a range of potential applications for treating chronic diseases via custom-designed cells that express therapeutic transgenes in response to dynamically changing biological signals.
Language	English
Publishing date	2021-09-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abj1414
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Article ; Online: Genome Engineering of Stem Cells for Autonomously Regulated, Closed-Loop Delivery of Biologic Drugs.

Brunger, Jonathan M / Zutshi, Ananya / Willard, Vincent P / Gersbach, Charles A / Guilak, Farshid

Stem cell reports

2017 Volume 8, Issue 5, Page(s) 1202–1213

Abstract: Chronic inflammatory diseases such as arthritis are characterized by dysregulated responses to pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α). Pharmacologic anti-cytokine therapies are often effective at ... ...

Abstract	Chronic inflammatory diseases such as arthritis are characterized by dysregulated responses to pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α). Pharmacologic anti-cytokine therapies are often effective at diminishing this inflammatory response but have significant side effects and are used at high, constant doses that do not reflect the dynamic nature of disease activity. Using the CRISPR/Cas9 genome-engineering system, we created stem cells that antagonize IL-1- or TNF-α-mediated inflammation in an autoregulated, feedback-controlled manner. Our results show that genome engineering can be used successfully to rewire endogenous cell circuits to allow for prescribed input/output relationships between inflammatory mediators and their antagonists, providing a foundation for cell-based drug delivery or cell-based vaccines via a rapidly responsive, autoregulated system. The customization of intrinsic cellular signaling pathways in stem cells, as demonstrated here, opens innovative possibilities for safer and more effective therapeutic approaches for a wide variety of diseases.
MeSH term(s)	Animals ; Arthritis/therapy ; CRISPR-Cas Systems ; Cartilage/physiology ; Cells, Cultured ; Feedback, Physiological ; Gene Editing/methods ; Immunologic Factors/genetics ; Immunologic Factors/metabolism ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/metabolism ; Induced Pluripotent Stem Cells/transplantation ; Interleukin-1/genetics ; Interleukin-1/metabolism ; Mice ; Mice, Inbred C57BL ; Regeneration ; Stem Cell Transplantation/methods ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Immunologic Factors ; Interleukin-1 ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2017-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2017.03.022
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