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- Rodent Models
- Swine Models
Challenges and Considerations During In Vitro Production of Porcine Embryos
Chen et al., Cells. 2021.
https://pubmed.ncbi.nlm.nih.gov/34685749/
Genetically modified pigs have become valuable tools for generating advances in animal agriculture and human medicine. Importantly, in vitro production and manipulation of embryos is an essential step in the process of creating porcine models. As the in vitro environment is still suboptimal, it is imperative to examine the porcine embryo culture system from several angles to identify methods for improvement. Understanding metabolic characteristics of porcine embryos and considering comparisons with other mammalian species is useful for optimizing culture media formulations. Furthermore, stressors arising from the environment and maternal or paternal factors must be taken into consideration to produce healthy embryos in vitro. In this review, Chen et al progress stepwise through in vitro oocyte maturation, fertilization, and embryo culture in pigs to assess the status of current culture systems and address points where improvements can be made. Supported by ORIP (U42OD011140).
Limited Expansion of Human Hepatocytes in FAH/RAG2-Deficient Swine
Nelson et al., Tissue Engineering – Part A. 2021.
https://pubmed.ncbi.nlm.nih.gov/34309416/
The mammalian liver's regenerative ability has led researchers to engineer animals as incubators for expansion of human hepatocytes. Nelson et al. engineered immunodeficient swine to support expansion of human hepatocytes and identify barriers to their clinical application. Immunodeficient swine were engineered by knockout of the recombinase-activating gene 2 (RAG2) and fumarylacetoacetate hydrolase (FAH). Immature human hepatocytes (ihHCs) were injected into fetal swine by intrauterine cell transplantation (IUCT) at day 40 of gestation. They identified the mechanism of the eventual graft rejection by the intact NK cell population. They confirmed the presence of residual adaptive immunity in this model of immunodeficiency. Supported by ORIP (U42OD011140).
Comparative Cellular Analysis of Motor Cortex in Human, Marmoset and Mouse
Bakken et al., Nature. 2021.
https://pubmed.ncbi.nlm.nih.gov/34616062/
Investigators used high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmosets, and mice, to characterize the cellular makeup of the primary motor cortex (M1), which exhibits similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. Despite the overall conservation, many species-dependent specializations are apparent. These results demonstrate the robust molecular foundations of cell-type diversity in M1 across mammals and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations. Supported by ORIP (P51OD010425), NIMH, NCATS, NINDS, and NIDA.
Genetic Basis For an Evolutionary Shift From Ancestral Preaxial to Postaxial Limb Polarity in Non-urodele Vertebrates
Trofka et al., Current Biology. 2021.
https://www.sciencedirect.com/science/article/pii/S0960982221012501
In most tetrapod vertebrates, limb skeletal progenitors condense with postaxial dominance. Posterior elements (ulna and fibula) appear prior to their anterior counterparts (radius and tibia), followed by digit-appearance order with continuing postaxial polarity. Recent fossil evidence suggests that preaxial polarity represents an ancestral rather than derived state. These authors report that 5'Hoxd (Hoxd11-d13) gene deletion in mouse is atavistic and uncovers an underlying preaxial polarity in mammalian limb formation. Evolutionary changes in Gli3R activity level, key in the fin-to-limb transition, appear to be fundamental to the shift from preaxial to postaxial polarity in formation of the tetrapod limb skeleton. Supported by ORIP (P40OD01979) and NCI.
Neuropeptide S Receptor 1 is a Nonhormonal Treatment Target in Endometriosis
Tapmeier et al., Science Translational Medicine. 2021.
https://pubmed.ncbi.nlm.nih.gov/34433639
Investigators analyzed genetic sequences of humans (n=32 families) and pedigree rhesus macaques (n=849) with spontaneous endometriosis to uncover potential targets for treatment. Target associations indicated a common insertion/deletion variant in NPSR1, the gene encoding neuropeptide S receptor 1. Immunocytochemistry, RT-PCR, and flow cytometry experiments indicated NPSR1 was expressed in the glandular epithelium of eutopic and ectopic endometrium. In a mouse model for endometriosis, an inhibitor of NPSR1-mediated signaling blocked proinflammatory TNFα release, monocyte chemotaxis, and inflammatory cell infiltrate. Further studies in nonhuman primates are needed; however, these results provide support for a nonhormonal treatment of endometriosis. Supported by ORIP (R24OD011173, P51OD011106).
A Noncoding RNA Modulator Potentiates Phenylalanine Metabolism in Mice
Li et al., Science. 2021.
https://pubmed.ncbi.nlm.nih.gov/34353949/
The role of long noncoding RNAs (lncRNAs) in phenylketonuria (PKU), an inherited disorder causing build-up of an amino acid causing brain problems, is unknown. Investigators demonstrated that the mouse lncRNA Pair and human lncRNA HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited phenotypes that faithfully models human PKU, such as excessive blood phenylalanine (Phe), growth retardation, and progressive neurological symptoms. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes (i.e., that have the capacity to self-renew by dividing). To develop a strategy for restoring liver lncRNAs, these investigators designed lncRNA mimics that exhibit liver enrichment. Treatment with these mimics reduced excessive Phe in Pair -/- and PAH R408W/R408W mice and improved the Phe tolerance of these mice. Supported by ORIP (S10OD012304) and others.
Sexual Dimorphic Impact of Adult-Onset Somatopause on Life Span and Age-Induced Osteoarthritis
Poudel et al., Aging Cell. 2021.
https://pubmed.ncbi.nlm.nih.gov/?term=Poudel%20SB&cauthor_id=34240807
Osteoarthritis (OA) is a major cause of disability worldwide. In humans, the age-associated decline in growth hormone (GH) levels was hypothesized to play a role in the etiology of OA. Investigators studied the impact of adult-onset isolated GH deficiency (AOiGHD) on the life span and skeletal integrity in aged mice. Reductions in GH during adulthood were associated with extended life span and reductions in body temperature in female mice only. However, end-of-life pathology revealed high levels of lymphomas in both sexes, independent of GH status. Skeletal characterization revealed increases in OA severity in AOiGHD mice. In conclusion, while their life span increased, AOiGHD female mice’s health span was compromised by high-grade lymphomas and the development of severe OA. In contrast, AOiGHD males, which did not show extended life span, showed an overall low grade of lymphomas but exhibited significantly decreased health span, evidenced by increased OA severity. Supported by ORIP (S10OD010751) and others.
Factor XII Plays a Pathogenic Role in Organ Failure and Death in Baboons Challenged with Staphylococcus aureus
Silasi et al., Blood. 2021.
https://pubmed.ncbi.nlm.nih.gov/33598692/
Activation of coagulation factor (F) XI promotes multiorgan failure in rodent models of sepsis and in a baboon model for lethal systemic inflammation induced by infusion of heat-inactivated Staphylococcus aureus. The authors used the anticoagulant FXII-neutralizing antibody 5C12 to verify the mechanistic role of FXII. Inhibition of FXII prevented fever, terminal hypotension, respiratory distress, and multiorgan failure. All animals receiving 5C12 had milder and transient clinical symptoms; untreated control animals suffered irreversible multiorgan failure. This study confirms their previous finding that at least two enzymes of FXIa and FXIIa play critical roles in the development of an acute and terminal inflammatory response. Supported by ORIP (P40OD024628), NIAID, NHLBI, and NIGMS.
Innate Immunity Stimulation via CpG Oligodeoxynucleotides Ameliorates Alzheimer’s Disease Pathology in Aged Squirrel Monkeys
Patel et al., Brain: A Journal of Neurology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34128045/
Alzheimer's disease is the only illness among the top 10 causes of death for which there is no disease-modifying therapy. The authors have shown in transgenic Alzheimer's disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-β, tau pathology, and cerebral amyloid angiopathy (CAA). They used a nonhuman primate model for sporadic Alzheimer's disease pathology that develops extensive CAA-elderly squirrel monkeys. They demonstrate that long-term use of Class B CpG ODN 2006 induces a favorable degree of innate immunity stimulation. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. This evidence together with their earlier research validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach. Supported by ORIP (P40OD010938), NINDS, NIA, and NCI.
In Vitro and In Vivo Functions of SARS-CoV-2 Infection-Enhancing and Neutralizing Antibodies
Li et al., Cell. 2021.
https://doi.org/10.1016/j.cell.2021.06.021
Antibody-dependent enhancement of infection is a concern for clinical use of antibodies. Researchers isolated neutralizing antibodies against the receptor-binding domain (RBD) or N-terminal domain (NTD) of SARS-CoV-2 spike from COVID-19 patients. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific binding modes. RBD and NTD antibodies mediated both neutralization and infection enhancement in vitro. However, infusion of these antibodies into mice or macaques resulted in suppression of virus replication, demonstrating that antibody-enhanced infection in vitro does not necessarily predict enhanced infection in vivo. RBD-neutralizing antibodies having cross-reactivity against coronaviruses were protective against SARS-CoV-2, the most potent of which was DH1047. Supported by ORIP (P40OD012217, U42OD021458, S10OD018164), NIAID, NCI, NIGMS, and NIH Common Fund.