Mouse background genetics in biomedical research: The devil's in the details

Hay, Ariel; Howie, Heather L.; Gorham, James D.; D’Alessandro, Angelo; Spitalnik, Steven L.; Hudson, Krystalyn E.; Zimring, James C.

doi:10.1111/trf.16628

Cited by 10 publications

(8 citation statements)

References 47 publications

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“…As such, the present study may represent an exercise in testing whether specific-pathways are indicative of earlier qualitative decay of the guinea pig RBCs. In other rodents ( Hay et al, 2021 ) and in humans ( Page et al, 2021 ), genetic heterogeneity of the blood donor pool was identified as a significant contributor to the biological variability in blood storage quality; although only one guinea pig strain was tested in the current study, this aspect could be evaluated further in the future. The average age of the guinea pigs tested in this study was ∼2.5 months old (young), which could impact the interpretation of the comparison to the other non-human primates at 5 years of age (young) or humans at age 30–75 (young adults to older age adults), owing to the well-established impact of age on the metabolome of stored RBCs ( D’Alessandro et al, 2021a ).…”

Section: Discussionmentioning

confidence: 99%

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Guinea Pigs, Humans, and Non-human Primates During Refrigerated Storage for Up to 42 Days

et al. 2022

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Unlike other rodents, guinea pigs (Cavia porcellus) have evolutionarily lost their capacity to synthesize vitamin C (ascorbate) de novo and, like several non-human primates and humans, rely on dietary intake and glutathione-dependent recycling to cope with oxidant stress. This is particularly relevant in red blood cell physiology, and especially when modeling blood storage, which exacerbates erythrocyte oxidant stress. Herein we provide a comprehensive metabolomics analysis of fresh and stored guinea pig red blood cell concentrates (n = 20), with weekly sampling from storage day 0 through 42. Results were compared to previously published ZOOMICS studies on red blood cells from three additional species with genetic loss of L-gulonolactone oxidase function, including humans (n = 21), olive baboons (n = 20), and rhesus macaques (n = 20). While metabolic trends were comparable across all species, guinea pig red blood cells demonstrated accelerated alterations of the metabolic markers of the storage lesion that are consistent with oxidative stress. Compared to the other species, guinea pig red blood cells showed aberrant glycolysis, pentose phosphate pathway end product metabolites, purine breakdown products, methylation, glutaminolysis, and markers of membrane lipid remodeling. Consistently, guinea pig red blood cells demonstrated higher end storage hemolysis, and scanning electron microscopy confirmed a higher degree of morphological alterations of their red blood cells, as compared to the other species. Despite a genetic inability to produce ascorbate that is common to the species evaluated, guinea pig red blood cells demonstrate accelerated oxidant stress under standard storage conditions. These data may offer relevant insights into the basal and cold storage metabolism of red blood cells from species that cannot synthesize endogenous ascorbate.

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Section: Discussionmentioning

confidence: 99%

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Guinea Pigs, Humans, and Non-human Primates During Refrigerated Storage for Up to 42 Days

et al. 2022

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“…Interestingly, passive immunization with IgG2c anti-HOD mAb induced higher levels of enhancement in Fc γ RIII -/- than in FcγRIII +/+ mice. The reason for this difference is unclear, as Fc γ RIII +/+ is not typically considered inhibitory; however, it could be the result of decreased competition with Fc γ RIV for the common γ chain required for Fc γ R signaling or contributions of the background genetics ( 29 ), which may influence immune responses.…”

Section: Discussionmentioning

confidence: 99%

FcγRIV is required for IgG2c mediated enhancement of RBC alloimmunization

et al. 2022

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Passive immunization with anti-D can prevent maternal alloimmunization to RhD thereby preventing hemolytic disease of the fetus and newborn. Unexpectedly, anti-D fails in some cases and some monoclonal anti-D preparations paradoxically enhances alloimmunization. The underlying mechanisms modulating humoral alloimmunization by anti-D are unknown. We previously reported that IgG antibody subclasses differentially regulate alloimmunity in response to red blood cell (RBC) transfusions in a mouse model; in particular, IgG2c significantly enhanced RBC alloantibody responses. Initial mechanistic studies revealed that IgG2c:RBC immune complexes were preferentially consumed by the splenic dendritic cell (DC) subsets that play a role in RBC alloimmunization. The deletion of activating Fc-gamma receptors (FcγRs) (i.e., FcγRI, FcγRIII, and FcγRIV) on DCs abrogated IgG2c-mediated enhanced alloimmunization. Because DCs express high levels of FcγRIV, which has high affinity for the IgG2c subclass, we hypothesized that FcγRIV was required for enhanced alloimmunization. To test this hypothesis, knockout mice and blocking antibodies were used to manipulate FcγR expression. The data presented herein demonstrate that FcγRIV, but not FcγRI or FcγRIII, is required for IgG2c-mediated enhancement of RBC alloantibody production. Additionally, FcγRI is alone sufficient for IgG2c-mediated RBC clearance but not for increased alloimmunization, demonstrating that RBC clearance can occur without inducing alloimmunization. Together, these data, combined with prior observations, support the hypothesis that passive immunization with an RBC-specific IgG2c antibody increases RBC alloantibody production through FcγRIV ligation on splenic conventional DCs (cDCs). This raises the question of whether standardizing antibody subclasses in immunoprophylaxis preparations is desirable and suggests which subclasses may be optimal for generating monoclonal anti-D therapeutics.

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“…This would be particularly beneficial in the N background before spending time and resources to backcross to a more susceptible strain such as BALB/cJ or 129/SvJ. This is also relevant as backcrossing into a different strain often leads to residual differences in the genetic background, if one compares the knock-out on the backcrossed strain with the wildtype of that strain ( Hay et al, 2021 ). Second, the model of modest proteinuria and nephropathy in the J substrain could potentially be a favorable model for certain reverse genetics, where the expectation is the exacerbation of injury with a double hit or insult such as knock-out or knock-in of relevant genes critical for podocyte function.…”

Section: Discussionmentioning

confidence: 99%

Adriamycin-Induced Nephropathy is Robust in N and Modest in J Substrain of C57BL/6

Bryant

Cianciolo²,

Govindarajan³

et al. 2022

Front. Cell Dev. Biol.

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Adriamycin (ADR)-induced nephropathy remains the leading model to study human primary focal segmental glomerulosclerosis (FSGS), a common pathway for podocyte damage and glomerular loss of function that leads to chronic kidney disease. However, the use of this model for reverse genetics is limited by historical categorization of C57BL/6 mice as an ADR-resistant strain, which is also the most common genetically modified strain. Additionally, conflicting reports exist utilizing C57BL/6 for ADR-nephrosis due to lack of understanding of substrain differences (J/N) and variability in ADR dosage, timing, and frequency to induce damage. We have undertaken a systematic approach to elucidate the specifics of ADR-nephrosis in C57BL/6 N and J substrains. We induced nephropathy with 2 doses of ADR, and measured albuminuria for 6 weeks and performed histological evaluations. Our findings revealed induction of robust and modest proteinuria in N and J substrains, respectively. The serum creatinine levels were elevated in N, but not J substrain. Both the substrains showed reduction in body weight with N greater than J, although mortality remained at 0% in both substrains. Histological analysis showed worse renal lesions in the N than the J substrain. Podocyte markers synaptopodin, nephrin, podocin, and WT1 were reduced to a greater extent in the N than the J substrain. In summary, we provide the nephrology community with a reproducible mouse model for FSGS, in a strain otherwise assumed to be ADR-resistant and highlight the differences between J and N substrains. This enables future studies, especially concerning genetically manipulated animal models in C57BL/6.

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Mouse background genetics in biomedical research: The devil's in the details

Cited by 10 publications

References 47 publications

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Guinea Pigs, Humans, and Non-human Primates During Refrigerated Storage for Up to 42 Days

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Guinea Pigs, Humans, and Non-human Primates During Refrigerated Storage for Up to 42 Days

FcγRIV is required for IgG2c mediated enhancement of RBC alloimmunization

Adriamycin-Induced Nephropathy is Robust in N and Modest in J Substrain of C57BL/6

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