Muench, M. O. | Search bioRxiv

bioRxiv2020

μ-Lat: A High-Throughput Humanized Mouse Model for Preclinical Evaluation of Human Immunodeficiency Virus Eradication Strategies

A critical barrier to the development of a human immunodeficiency virus (HIV) cure is the lack of a scalable animal model that enables robust evaluation of eradication approaches prior to testing in humans. We established a humanized mouse model of latent HIV infection by transplanting "J-Lat" cells, Jurkat cells harboring a latent HIV provirus encoding an enhanced green fluorescent protein (GFP) reporter, into irradiated adult NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. J-Lat cells exhibited successful engraftment in several tissues including spleen, bone barrow, peripheral blood, and lung, in line with the diverse natural tissue tropism of HIV. Administration of tumor necrosis factor (TNF)-, an established HIV latency reversal agent, significantly induced GFP expression in engrafted cells across tissues, reflecting viral reactivation. These data suggest that our murine latency ("-Lat") model enables efficient determination of how effectively viral eradication agents, including latency reversal agents, penetrate and function in diverse anatomical sites harboring HIV in vivo.

microbiology↗

bioRxiv2018

Diverse progenitor cells preserve salivary gland ductal architecture after radiation induced damage

The ductal system of the salivary gland has long been postulated to be resistant to radiation-induced damage, a common outcome incurred by head and neck cancer patients receiving radiotherapy. Yet, whether the ducts are capable of regenerating after genotoxic injury, or if damage to ductal cells induces lineage plasticity, as has been reported in other organ systems, remains unknown. Here, we show that two ductal progenitor populations marked by KRT14 and KIT exclusively maintain non-overlapping ductal compartments after radiation exposure but do so through distinct cellular mechanisms. KRT14+ progenitor cells are fast cycling cells that proliferate in response to radiation-induced damage in a sustained manner and divide asymmetrically to produce differentiated cells of the larger granulated ducts. Conversely, KIT+ cells are long lived progenitors for the intercalated ducts that undergo few cell divisions either during homeostasis or after gamma radiation, thus maintaining ductal architecture in the near absence of cell turnover. Together, these data illustrate the regenerative capacity of the salivary ducts and highlight the heterogeneity in the damage responses used by salivary progenitor cells to maintain tissue architecture.\n\nSummary StatementThe salivary gland ductal network is maintained during homeostasis and after genotoxic injury by diverse progenitors that respond differentially to radiation induced damage.

developmental biology↗