Liver organoids in domestic animals: an expected promise for metabolic studies.

The liver is one of the most important organs, both in terms of the different metabolic processes (energy, lipid, ferric, uric, etc.) and of its central role in the processes of detoxification of substances of food origin or noxious substances (alcohol, drugs, antibiotics, etc.). The development of a relevant model that reproduces some of the functions of this tissue has become a challenge, in particular for human medicine. Thus, in recent years, most studies aimed at producing hepatocytes in vitro with the goal of developing hepatic 3D structures have been carried out in the human model. However, the tools and protocols developed using this unique model can also be considered to address physiological questions specific to this tissue in other species, such as the pig, chicken, and duck. Different strategies are presently being considered to carry out in vitro studies of the hepatic metabolism of these agronomic species.

Cerebral organoids and their potential for studies of brain diseases in domestic animals.

The brain is a complex organ and any model for studying it in its normal and pathological aspects becomes a tool of choice for neuroscientists. The mastering and dissemination of protocols allowing brain organoids development have paved the way for a whole range of new studies in the field of brain development, modeling of neurodegenerative or neurodevelopmental diseases, understanding tumors as well as infectious diseases that affect the brain. While studies are so far limited to the use of human cerebral organoids, there is a growing interest in having similar models in other species. This review presents what is currently developed in this field, with a particular focus on the potential of cerebral organoids for studying neuro-infectious diseases in human and domestic animals.

STLV-1 Commonly Targets Neurons in the Brain of Asymptomatic Non-Human Primates.

The human T-cell leukemia virus (HTLV)-1 is responsible for an aggressive neurodegenerative disease (HAM/TSP) and multiple neurological alterations. The capacity of HTLV-1 to infect central nervous system (CNS) resident cells, together with the neuroimmune-driven response, has not been well-established. Here, we combined the use of human induced pluripotent stem cells (hiPSC) and of naturally STLV-1-infected nonhuman primates (NHP) as models with which to investigate HTLV-1 neurotropism. Hence, neuronal cells obtained after hiPSC differentiation in neural polycultures were the main cell population infected by HTLV-1. Further, we report the infection of neurons with STLV-1 in spinal cord regions as well as in brain cortical and cerebellar sections of postmortem NHP. Additionally, reactive microglial cells were found in infected areas, suggesting an immune antiviral response. These results emphasize the need to develop new efficient models by which to understand HTLV-1 neuroinfection and suggest an alternative mechanism that leads to HAM/TSP.

Human Brain Organoids-on-Chip: Advances, Challenges, and Perspectives for Preclinical Applications.

There is an urgent need for predictive in vitro models to improve disease modeling and drug target identification and validation, especially for neurological disorders. Cerebral organoids, as alternative methods to in vivo studies, appear now as powerful tools to decipher complex biological processes thanks to their ability to recapitulate many features of the human brain. Combining these innovative models with microfluidic technologies, referred to as brain organoids-on-chips, allows us to model the microenvironment of several neuronal cell types in 3D. Thus, this platform opens new avenues to create a relevant in vitro approach for preclinical applications in neuroscience. The transfer to the pharmaceutical industry in drug discovery stages and the adoption of this approach by the scientific community requires the proposition of innovative microphysiological systems allowing the generation of reproducible cerebral organoids of high quality in terms of structural and functional maturation, and compatibility with automation processes and high-throughput screening. In this review, we will focus on the promising advantages of cerebral organoids for disease modeling and how their combination with microfluidic systems can enhance the reproducibility and quality of these in vitro models. Then, we will finish by explaining why brain organoids-on-chips could be considered promising platforms for pharmacological applications.

Intranasal Exposure to Rift Valley Fever Virus Live-Attenuated Strains Leads to High Mortality Rate in Immunocompetent Mice.

Rift Valley fever virus (RVFV) is a pathogenic arthropod-borne virus that can cause serious illness in both ruminants and humans. The virus can be transmitted by an arthropod bite or contact with contaminated fluids or tissues. Two live-attenuated veterinary vaccines-the Smithburn (SB) and Clone 13 (Cl.13)-are currently used during epizootic events in Africa. However, their residual pathogenicity (i.e., SB) or potential of reversion (i.e., Cl.13) causes important adverse effects, strongly limiting their use in the field. In this study, we infected immunocompetent mice with SB or Cl.13 by a subcutaneous or an intranasal inoculation. Interestingly, we found that, unlike the subcutaneous infection, the intranasal inoculation led to a high mortality rate. In addition, we detected high titers and viral N antigen levels in the brain of both the SB- and Cl.13-infected mice. Overall, we unveil a clear correlation between the pathogenicity and the route of administration of both SB and Cl.13, with the intranasal inoculation leading to a stronger neurovirulence and higher mortality rate than the subcutaneous infection.

Reprogrammed Pteropus Bat Stem Cells as A Model to Study Host-Pathogen Interaction during Henipavirus Infection.

Bats are natural hosts for numerous zoonotic viruses, including henipaviruses, which are highly pathogenic for humans, livestock, and other mammals but do not induce clinical disease in bats. Pteropus bats are identified as a reservoir of henipaviruses and the source of transmission of the infection to humans over the past 20 years. A better understanding of the molecular and cellular mechanisms allowing bats to control viral infections requires the development of relevant, stable, and permissive cellular experimental models. By applying a somatic reprogramming protocol to Pteropus bat primary cells, using a combination of ESRRB (Estrogen Related Receptor Beta), CDX2 (Caudal type Homeobox 2), and c-MYC (MYC proto-oncogene) transcription factors, we generated bat reprogrammed cells. These cells exhibit stem cell-like characteristics and neural stem cell molecular signature. In contrast to primary fibroblastic cells, these reprogrammed stem cells are highly permissive to henipaviruses and exhibit specific transcriptomic profiles with the particular expression of certain susceptibility factors such as interferon-stimulated genes (ISG), which may be related to viral infection. These Pteropus bat reprogrammed stem cells should represent an important experimental tool to decipher interactions during henipaviruses infection in Pteropus bats, facilitate isolation and production of bat-borne viruses, and to better understand the bat biology.

Antisense-Based Progerin Downregulation in HGPS-Like Patients' Cells.

Progeroid laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670), are premature and accelerated aging diseases caused by defects in nuclear A-type Lamins. Most HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type Lamins. This mutation activates a cryptic splice site leading to the deletion of 50 amino acids at its carboxy-terminal domain, resulting in a truncated and permanently farnesylated Prelamin A called Prelamin A Δ50 or Progerin. Some patients carry other LMNA mutations affecting exon 11 splicing and are named "HGPS-like" patients. They also produce Progerin and/or other truncated Prelamin A isoforms (Δ35 and Δ90) at the transcriptional and/or protein level. The results we present show that morpholino antisense oligonucleotides (AON) prevent pathogenic LMNA splicing, markedly reducing the accumulation of Progerin and/or other truncated Prelamin A isoforms (Prelamin A Δ35, Prelamin A Δ90) in HGPS-like patients' cells. Finally, a patient affected with Mandibuloacral Dysplasia type B (MAD-B, carrying a homozygous mutation in ZMPSTE24, encoding an enzyme involved in Prelamin A maturation, leading to accumulation of wild type farnesylated Prelamin A), was also included in this study. These results provide preclinical proof of principle for the use of a personalized antisense approach in HGPS-like and MAD-B patients, who may therefore be eligible for inclusion in a therapeutic trial based on this approach, together with classical HGPS patients.