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  1. Article ; Online: Viral airway injury promotes cell engraftment in an in vitro model of cystic fibrosis cell therapy.

    Lee, Rhianna E / Mascenik, Teresa M / Major, Sidra C / Galiger, Jacob R / Bulik-Sullivan, Emily / Siesser, Priscila F / Lewis, Catherine A / Bear, James E / Le Suer, Jake A / Hawkins, Finn J / Pickles, Raymond J / Randell, Scott H

    American journal of physiology. Lung cellular and molecular physiology

    2023  Volume 326, Issue 3, Page(s) L226–L238

    Abstract: Cell therapy is a potential treatment for cystic fibrosis (CF). However, cell engraftment into the airway epithelium is challenging. Here, we model cell engraftment in vitro using the air-liquid interface (ALI) culture system by injuring well- ... ...

    Abstract Cell therapy is a potential treatment for cystic fibrosis (CF). However, cell engraftment into the airway epithelium is challenging. Here, we model cell engraftment in vitro using the air-liquid interface (ALI) culture system by injuring well-differentiated CF ALI cultures and delivering non-CF cells at the time of peak injury. Engraftment efficiency was quantified by measuring chimerism by droplet digital PCR and functional ion transport in Ussing chambers. Using this model, we found that human bronchial epithelial cells (HBECs) engraft more efficiently when they are cultured by conditionally reprogrammed cell (CRC) culture methods. Cell engraftment into the airway epithelium requires airway injury, but the extent of injury needed is unknown. We compared three injury models and determined that severe injury with partial epithelial denudation facilitates long-term cell engraftment and functional CFTR recovery up to 20% of wildtype function. The airway epithelium promptly regenerates in response to injury, creating competition for space and posing a barrier to effective engraftment. We examined competition dynamics by time-lapse confocal imaging and found that delivered cells accelerate airway regeneration by incorporating into the epithelium. Irradiating the repairing epithelium granted engrafting cells a competitive advantage by diminishing resident stem cell proliferation. Intentionally, causing severe injury to the lungs of people with CF would be dangerous. However, naturally occurring events like viral infection can induce similar epithelial damage with patches of denuded epithelium. We found that viral preconditioning promoted effective engraftment of cells primed for viral resistance.
    MeSH term(s) Humans ; Cystic Fibrosis/therapy ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Epithelium ; Epithelial Cells ; Cell- and Tissue-Based Therapy ; Virus Diseases ; Cells, Cultured
    Chemical Substances Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
    Language English
    Publishing date 2023-12-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1013184-x
    ISSN 1522-1504 ; 1040-0605
    ISSN (online) 1522-1504
    ISSN 1040-0605
    DOI 10.1152/ajplung.00421.2022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Airway stem cell reconstitution by the transplantation of primary or pluripotent stem cell-derived basal cells.

    Ma, Liang / Thapa, Bibek R / Le Suer, Jake A / Tilston-Lünel, Andrew / Herriges, Michael J / Berical, Andrew / Beermann, Mary Lou / Wang, Feiya / Bawa, Pushpinder S / Kohn, Anat / Ysasi, Alexandra B / Kiyokawa, Hirofumi / Matte, Taylor M / Randell, Scott H / Varelas, Xaralabos / Hawkins, Finn J / Kotton, Darrell N

    Cell stem cell

    2023  Volume 30, Issue 9, Page(s) 1199–1216.e7

    Abstract: Life-long reconstitution of a tissue's resident stem cell compartment with engrafted cells has the potential to durably replenish organ function. Here, we demonstrate the engraftment of the airway epithelial stem cell compartment via intra-airway ... ...

    Abstract Life-long reconstitution of a tissue's resident stem cell compartment with engrafted cells has the potential to durably replenish organ function. Here, we demonstrate the engraftment of the airway epithelial stem cell compartment via intra-airway transplantation of mouse or human primary and pluripotent stem cell (PSC)-derived airway basal cells (BCs). Murine primary or PSC-derived BCs transplanted into polidocanol-injured syngeneic recipients give rise for at least two years to progeny that stably display the morphologic, molecular, and functional phenotypes of airway epithelia. The engrafted basal-like cells retain extensive self-renewal potential, evident by the capacity to reconstitute the tracheal epithelium through seven generations of secondary transplantation. Using the same approach, human primary or PSC-derived BCs transplanted into NOD scid gamma (NSG) recipient mice similarly display multilineage airway epithelial differentiation in vivo. Our results may provide a step toward potential future syngeneic cell-based therapy for patients with diseases resulting from airway epithelial cell damage or dysfunction.
    MeSH term(s) Humans ; Animals ; Mice ; Pluripotent Stem Cells ; Cell- and Tissue-Based Therapy ; Epithelial Cells ; Epithelium ; Mice, Inbred NOD ; Mice, SCID
    Language English
    Publishing date 2023-08-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2375354-7
    ISSN 1875-9777 ; 1934-5909
    ISSN (online) 1875-9777
    ISSN 1934-5909
    DOI 10.1016/j.stem.2023.07.014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A multimodal iPSC platform for cystic fibrosis drug testing.

    Berical, Andrew / Lee, Rhianna E / Lu, Junjie / Beermann, Mary Lou / Le Suer, Jake A / Mithal, Aditya / Thomas, Dylan / Ranallo, Nicole / Peasley, Megan / Stuffer, Alex / Bukis, Katherine / Seymour, Rebecca / Harrington, Jan / Coote, Kevin / Valley, Hillary / Hurley, Killian / McNally, Paul / Mostoslavsky, Gustavo / Mahoney, John /
    Randell, Scott H / Hawkins, Finn J

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 4270

    Abstract: Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established ... ...

    Abstract Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established animal and cell-based models led to the recent discovery of effective modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we generate a panel of airway epithelial cells using induced pluripotent stem cells from individuals with common or rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function we adapt two established in vitro assays for use in induced pluripotent stem cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect genotype-specific differences in CFTR baseline function and response to CFTR modulators. These results demonstrate the potential of the human induced pluripotent stem cell platform as a research tool to study CF and in particular accelerate therapeutic development for CF caused by rare variants.
    MeSH term(s) Animals ; Cystic Fibrosis/drug therapy ; Cystic Fibrosis/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Epithelial Cells/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Ion Transport
    Chemical Substances Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
    Language English
    Publishing date 2022-07-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-31854-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Protection against a mixed SHIV challenge by a broadly neutralizing antibody cocktail.

    Julg, Boris / Liu, Po-Ting / Wagh, Kshitij / Fischer, William M / Abbink, Peter / Mercado, Noe B / Whitney, James B / Nkolola, Joseph P / McMahan, Katherine / Tartaglia, Lawrence J / Borducchi, Erica N / Khatiwada, Shreeya / Kamath, Megha / LeSuer, Jake A / Seaman, Michael S / Schmidt, Stephen D / Mascola, John R / Burton, Dennis R / Korber, Bette T /
    Barouch, Dan H

    Science translational medicine

    2017  Volume 9, Issue 408

    Abstract: HIV-1 sequence diversity presents a major challenge for the clinical development of broadly neutralizing antibodies (bNAbs) for both therapy and prevention. Sequence variation in critical bNAb epitopes has been observed in most HIV-1-infected individuals ...

    Abstract HIV-1 sequence diversity presents a major challenge for the clinical development of broadly neutralizing antibodies (bNAbs) for both therapy and prevention. Sequence variation in critical bNAb epitopes has been observed in most HIV-1-infected individuals and can lead to viral escape after bNAb monotherapy in humans. We show that viral sequence diversity can limit both the therapeutic and prophylactic efficacy of bNAbs in rhesus monkeys. We first demonstrate that monotherapy with the V3 glycan-dependent antibody 10-1074, but not PGT121, results in rapid selection of preexisting viral variants containing N332/S334 escape mutations and loss of therapeutic efficacy in simian-HIV (SHIV)-SF162P3-infected rhesus monkeys. We then show that the V3 glycan-dependent antibody PGT121 alone and the V2 glycan-dependent antibody PGDM1400 alone both fail to protect against a mixed challenge with SHIV-SF162P3 and SHIV-325c. In contrast, the combination of both bNAbs provides 100% protection against this mixed SHIV challenge. These data reveal that single bNAbs efficiently select resistant viruses from a diverse challenge swarm to establish infection, demonstrating the importance of bNAb cocktails for HIV-1 prevention.
    MeSH term(s) Amino Acid Sequence ; Animals ; Antibodies, Neutralizing/chemistry ; Antibodies, Neutralizing/therapeutic use ; Base Sequence ; Epitopes/immunology ; Gene Products, env/chemistry ; Gene Products, env/genetics ; HIV-1/immunology ; Inhibitory Concentration 50 ; Macaca mulatta ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Acquired Immunodeficiency Syndrome/prevention & control ; Simian Acquired Immunodeficiency Syndrome/virology ; Simian Immunodeficiency Virus/immunology
    Chemical Substances Antibodies, Neutralizing ; Epitopes ; Gene Products, env
    Language English
    Publishing date 2017-09-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.aao4235
    Database MEDical Literature Analysis and Retrieval System OnLINE

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