Publications by authors named "K Candis Jones-Ungerleider"

3 Publications

  • Page 1 of 1

Engineered Fibroblast Extracellular Vesicles Attenuate Pulmonary Inflammation and Fibrosis in Bleomycin-Induced Lung Injury.

Front Cell Dev Biol 2021 23;9:733158. Epub 2021 Sep 23.

Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA, United States.

Pulmonary fibrosis is a progressive disease for which no curative treatment exists. We have previously engineered dermal fibroblasts to produce extracellular vesicles with tissue reparative properties dubbed activated specialized tissue effector extracellular vesicles (ASTEX). Here, we investigate the therapeutic utility of ASTEX and in a mouse model of bleomycin-induced lung injury. RNA sequencing demonstrates that ASTEX are enriched in micro-RNAs (miRs) cargo compared with EVs from untransduced dermal fibroblast EVs (DF-EVs). Treating primary macrophages with ASTEX reduced interleukin (IL)6 expression and increased IL10 expression compared with DF-EV-exposed macrophages. Furthermore, exposure of human lung fibroblasts or vascular endothelial cells to ASTEX reduced expression of smooth muscle actin, a hallmark of myofibroblast differentiation (respectively). , intratracheal administration of ASTEX in naïve healthy mice demonstrated a favorable safety profile with no changes in body weight, lung weight to body weight, fibrotic burden, or histological score 3 weeks postexposure. In an acute phase (short-term) bleomycin model of lung injury, ASTEX reduced lung weight to body weight, IL6 expression, and circulating monocytes. In a long-term setting, ASTEX improved survival and reduced fibrotic content in lung tissue. These results suggest potential immunomodulatory and antifibrotic properties of ASTEX in lung injury.
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http://dx.doi.org/10.3389/fcell.2021.733158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8512699PMC
September 2021

Casein-enhanced uptake and disease-modifying bioactivity of ingested extracellular vesicles.

J Extracell Vesicles 2021 01 11;10(3):e12045. Epub 2021 Jan 11.

Cedars-Sinai Medical Center Smidt Heart Institute Los Angeles California USA.

Extracellular vesicles (EVs) from cardiac stromal cells, developed as therapeutic candidates, improve dystrophic muscle function when administered parenterally, but oral delivery remains untested. We find that casein, the dominant protein in breast milk, enhances the uptake and bioactivity of ingested heart-derived EVs, altering gene expression in blood cells and enhancing muscle function in mice with muscular dystrophy. Thus, EVs, administered orally, are absorbed and exert disease-modifying bioactivity . Formulating EVs with casein enhances uptake and markedly expands the range of potential therapeutic applications.
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http://dx.doi.org/10.1002/jev2.12045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798403PMC
January 2021

Small molecule inhibitors and culture conditions enhance therapeutic cell and EV potency via activation of beta-catenin and suppression of THY1.

Nanomedicine 2021 04 13;33:102347. Epub 2020 Dec 13.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address:

Primary cell therapy continues to face significant hurdles to therapeutic translation including the inherent variations that exist from donor to donor, batch to batch, and scale-up driven modifications to the manufacturing process. Cardiosphere-derived cells (CDCs) are stromal/progenitor cells with clinically demonstrated tissue reparative capabilities. Mechanistic investigations have identified canonical Wnt/β-catenin signaling as a therapeutic potency marker, and THY1 (CD90) expression as inversely correlated with potency. Here we demonstrate that the cardiosphere formation process increases β-catenin levels and enriches for therapeutic miR content in the extracellular vesicles of these cells, namely miR-146a and miR-22. We further find that loss of potency is correlated with impaired cardiosphere formation. Finally, our data show that small GSK3β inhibitors including CHIR, and BIO and "pro-canonical Wnt" culturing conditions can rescue β-catenin signaling and reduce CD90 expression. These findings identify strategies that could be used to maintain CDC potency and therapeutic consistency.
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http://dx.doi.org/10.1016/j.nano.2020.102347DOI Listing
April 2021
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