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Heterozygous lipoprotein lipase knockout mice exhibit impaired hematopoietic stem/progenitor cell compartment

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animal models and experimental Medicine 2021年第4期4卷 418-425页

作者： Guiying Shi Xinyue Li Keya Li Yiying Huang Xuepei Lei Lin Bai Chuan Qin The Institute of Laboratory animal Sciences CAMS&PUMCBeijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesBeijingP.R.China

Background : Hematopoietic stem cells (HSC) maintain the hematopoietic system homeostasis through self- renewal and multilineage differentiation potential. HSC are regulated by the microenvironment, cytokine signaling, and transcription factors. Recent results have shown that lipid pathways play a key role in the regulation of HSC quiescence, proliferation, and division. However, the mechanism by which lipid metabolism regulates HSC proliferation and differentiation remains to be clarified. Lipoprotein lipase (LPL) is an essential enzyme in the anabolism and catabolism of very low- density lipoprotein, chylomicrons, and triglyceride- rich lipoproteins. Methods : The percentage of hematopoietic stem/progenitor cells and immune cells were determined by fluorescence- activated cell sorting (FACS). The function and the mechanism of HSCs were analyzed by cell colony forming assay and qPCR analysis. The changes in LPL^(+/−) HSC microenvironment were detected by transplantation as- says using red fluorescent protein (RFP) transgenic mice. Results : To explore the function of LPL in HSC regulation, heterozygous LPL- knockout mice (LPL^(+/−)) were established and analyzed by FACS. LPL^(+/−) mice displayed decreased hematopoietic stem/progenitor cell compartments. In vitro single- cell clono- genic assays and cell-cycle assays using FACS promoted the cell cycle and increased proliferation ability. qPCR analysis showed the expression of p57^(KIP2) and p21^(WAF1)/ ^(CIP1) in LPL^(+/−) mice was upregulated. Conclusions : LPL^(+/−) mice exhibited HSC compartment impairment due to promotion of HSC proliferation, without any effects on the bone marrow (BM) microenvironment.

关键词： cell cycle HSCs LPL

Stem cell therapy for Alzheimer’s disease:An overview of experimental models and reality

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animal models and experimental Medicine 2022年第1期5卷 15-26页

作者： Chuan Qin Kewei Wang Ling Zhang Lin Bai Institute of Laboratory animal Sciences Chinese Academy of Medical Sciences(CAMS)Comparative Medicine CenterPeking Union Medical College(PUMC)NHC Key Laboratory of Human Disease Comparative MedicineKey Laboratory of Human Diseases Animal ModelBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases BeijingBeijingChina

Alzheimer's disease(AD)is a neurodegenerative disorder.The pathology of AD is characterized by extracellular amyloid beta(Aβ)plaques,neurofibrillary tangles com-posed of hyperphosphorylated tau,neuronal death,synapse loss,and brain atrophy.Many therapies have been tested to improve or at least effectively modify the course of AD.Meaningful data indicate that the transplantation of stem cells can alleviate neuropathology and significantly ameliorate cognitive deficits in animal models with Alzheimer's disease.Transplanted stem cells have shown their inherent advantages in improving cognitive impairment and memory dysfunction,although certain weak-nesses or limitations need to be overcome.This review recapitulates rodent models for AD,the therapeutic efficacy of stem cells,influencing factors,and the underlying mechanisms behind these changes.Stem cell therapy provides perspective and chal-lenges for its clinical application in the future.

关键词： Alzheimer's disease animal model cognitive deficits memory loss stem cell therapy

Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer

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animal models and experimental Medicine 2023年第3期6卷 245-254页

作者： Yumin Wei Liping Zhang Chao Wang Zefeng Li Mingjie Luo Guomin Xie Xingjiu Yang Mengyuan Li Shuyue Ren Dongbing Zhao Ran Gao Jia-Nan Gong National human diseases animal Model Resource center The Institute of Laboratory Animal ScienceChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijingChina NHC Key Laboratory of human Disease Comparative Medicine Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesBeijingChina beijing engineering research center for experimental animal models of human critical diseases BeijingChina Department of Pancreatic and Gastric Surgical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina State Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-Sen UniversityGuangzhouChina

Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions. Method: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR(ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using(CellTiter-Glo) CTG assay in vitro. Western Blot(WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Coimmunoprecipitation(Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR(RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity. Results: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time-and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.Conclusion: We identified BCL-XL as a promising therapeutic target in a subset o

关键词： apoptosis BCL2L1(BCL-XL) gastric cancer(GC) PROTAC-BCL-XL selective BCL-XL inhibitors

Screening for urinary markers predicting hematopoietic stem cell injury induced by busulfan using genetically diverse mice

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animal models and experimental Medicine 2023年第2期6卷 146-154页

作者： Yuhang Sun Bowen Guan Xing Liu Lingyan Zhang Xinpei Wang Aimin Meng Ran Gao National human diseases animal Model Resource center NHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesInstitute of Laboratory Animal Sciences Chinese Academy of Medical Sciences(CAMS)and Peking Union Medical College(PUMC)National Center of Technology Innovation for Animal ModelBeijingChina

Background:Busulfan(BU)is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell(HSC)transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells.The susceptibility of HSCs to BU injury plays an important role in the myeloablative efficacy of BU.Different susceptibilities were demonstrated in genetically diverse(GD)mice in our preliminary research.Methods:Three strains of GD mice with different susceptibilities to BU-i nduced HSC injury were used for screening biological markers of HSC injury susceptibility in urine.The urine proteins were analyzed using liquid chromatography coupled with tandem mass spectrometry to screen for differentially expressed proteins.Screening for possible biomarkers based on differences in protein expression abundance was validated using enzyme-l inked immunoassay(ELISA).Results:Functional analysis showed that the differential proteins were all involved in a series of biological pathways related to cellular senescence,apoptosis,and angiogenesis;whereas the differential proteins of the high-susceptible strain were enriched for the regulation of bone marrow microenvironment pathways,those of low-susceptible strain were enriched for the proapoptotic effect of GTPase pathways.Based on protein abundance differences,several urinary proteins that may be indicative of susceptibility were screened,and ELISA validation results showed that angiotensin-converting enzyme may be a potential biomarker predicting HSC susceptibility for BU conditioning.Conclusions:This study indicates that urinary protein levels can reflect differences in susceptibility to BU-i nduced HSC injury.Using GD mice to construct genetic difference models will provide preclinical data for screening BU-related biological markers.

关键词： angiotensin I converting enzyme busulfan hematopoietic stem cell injury inbred genetic diversity mice urinary marker

Distinct neuronal excitability alterations of medial prefrontal cortex in early-life neglect model of rats

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animal models and experimental Medicine 2022年第3期5卷 274-280页

作者： Yu Zhang Xiuping Sun Changsong Dou Xianglei Li Ling Zhang Chuan Qin NHC Key Laboratory of human Disease Comparative Medicine Institute of Laboratory Animal SciencesChinese Academy of Medical Sciences(CAMS)Comparative Medicine CenterPeking Union Medical College(PUMC)BeijingChina National human diseases animal Model Resource center BeijingChina beijing engineering research center for experimental animal models of human critical diseases BeijingChina International center for Technology and Innovation of animal model BeijingChina Changping National laboratory(CPNL) BeijingChina

Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:Maternal separation with early weaning was used as a rat model of early-life neglect.The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole-cell patch clamp.Results:Glutamatergic and GABAergic neurons of mPFC were distinguished by typi-cal electrophysiological properties.The excitation of mPFC glutamatergic neurons was significantly increased in male groups,while the excitation of mPFC GABAergic neurons was significant in both female and male groups,but mainly in terms of rest membrane potential and amplitude,respectively.Conclusions:Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early-life neglect,which can contribute to distinct mechanisms for emotional and cognitive manifestations.

关键词： early-life neglect model GABAergic glutamatergic maternal separation with early weaning medial prefrontal cortex neuronal excitability

Autophagy and autophagy-related molecules in neurodegenerative diseases

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animal models and experimental Medicine 2023年第1期6卷 10-17页

作者： Changsong Dou Yu Zhang Ling Zhang Chuan Qin NHC Key Laboratory of human Disease Comparative Medicine Key Laboratory of Human Diseases Animal ModelInstitute of Laboratory Animal SciencesComparative Medicine CenterPeking Union Medical College(PUMC)Chinese Academy of Medical Sciences(CAMS)BeijingChina Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases Beijing Comparative Medicine CenterPeking Union Medical College(PUMC)Chinese Academy of Medical Sciences(CAMS)BeijingChina

Autophagy is one of the degradation pathways to remove proteins or damaged or-ganelles in cells that plays an important role in neuroprotection.Different stages of autophagy are regulated by autophagy-related genes,and many molecules such as transcription factor EB(TFEB)are involved.The complete autophagy process plays an important role in maintaining the dynamic balance of autophagy and is crucial to the homeostasis of intracellular substance and energy metabolism.Autophagy balance is disrupted in neurodegenerative diseases,accounting for a variety of degeneration dis-orders.These impairments can be alleviated or treated by the regulation of autophagy through molecules such as TFEB.

关键词： autophagy mitophagy neurodegenerative TFEB

Is China ready for monkeypox?

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animal models and experimental Medicine 2022年第4期5卷 397-398页

作者： Qiang Wei Institute of Laboratory animal Sciences Chinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijingChina NHC Key Laboratory of human Disease Comparative Medicine beijing engineering research center for experimental animal models of human critical diseases

Monkeypox is a rare viral infection caused by the monkeypox virus,which is similar to human smallpox.It is also a zoonosis which is found mainly in tropical rain forests of central and western Africa.The monkeypox virus was first detected in grivet at a laboratory in Copenhagen,Denmark,in 1958,and was later found in many African rodents,such as murine and squirrels.Therefore,it is believed that the primary way of infection is through direct human contact with these infected animals.In May 2003,human monkeypox appeared in the Western Hemisphere in the United States and spreaded rapidly,which immediately attracted the attention of all countries.

关键词： infection monkey Africa

TRDMT1 exhibited protective effects against LPS-induced inflammation in rats through TLR4-NF-κB/MAPK-TNF-αpathway

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animal models and experimental Medicine 2022年第2期5卷 172-182页

作者： Zhengguang Li Xiaolong Qi Xu Zhang Lei Yu Lijuan Gao Weining Kong Wei Chen Wei Dong Lijun Luo Dan Lu Lianfeng Zhang Yuanwu Ma Key Laboratory of human Disease Comparative Medicine National Health Commission of China(NHC)Institute of Laboratory Animal ScienceChinese Academy of Medical SciencesPeking Union Medicine CollegeBeijingChina National human diseases animal Model Resource center and beijing engineering research center for experimental animal models of human critical diseases Institute of Laboratory Animal SciencePeking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina Neuroscience center Chinese Academy of Medical SciencesBeijingChina

Background:Inflammation is a complex physiological and pathological process.Although many types of inflammation are well characterized,their physiological func-tions are largely unknown.tRNA aspartic acid methyltransferase 1(TRDMT1)has been implicated as a stress-related protein,but its intrinsic biological role is unclear.Methods:We constructed a Trdmt1 knockout rat and adopted the LPS-induced sepsis model.Survival curve,histopathological examination,expression of inflammatory fac-tors,and protein level of TLR4 pathway were analyzed.Results:Trdmt1 deletion had no obvious impact on development and growth.Trdmt1 de-letion slightly increased the mortality during aging.Our data showed that Trdmt1 strongly responded in LPS-treated rats,and Trdmt1 knockout rats were vulnerable to LPS treat-ment with declined survival rate.We also observed more aggravated tissue damage and more cumulative functional cell degeneration in LPS-treated knockout rats compared with control rats.Further studies showed upregulated TNF-αlevel in liver,spleen,lung,and serum tissues,which may be explained by enhanced p65 and p38 phosphorylation.Conclusions:Our data demonstrated that Trdmt1 plays a protective role in inflamma-tion by regulating the TLR4-NF-κB/MAPK-TNF-αpathway.This work provides useful information to understand the TRDMT1 function in inflammation.

关键词： inflammation knockout rat TLR4 pathway TNF-α Trdmt1

Novel spontaneous myelodysplastic syndrome mouse model

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animal models and experimental Medicine 2021年第2期4卷 169-180,I0002页

作者： Weisha Li Lin Cao Mengyuan Li Xingjiu Yang Wenlong Zhang Zhiqi Song Xinpei Wang Lingyan Zhang Grant Morahan Chuan Qin Ran Gao NHC Key Laboratory of human Disease Comparative Medicine Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesInstitute of Laboratory Animal SciencesChinese Academy of Medical Sciences(CAMS)and Comparative Medicine CenterPeking Union Medical College(PUMC)BeijingChina

Background:Myelodysplastic syndrome(MDS)is a group of disorders involving he-mopoietic dysfunction leading to leukemia.Although recently progress has been made in identifying underlying genetic mutations,many questions still remain.animal models of MDS have been produced by introduction of specific mutations.However,there is no spontaneous mouse model of MDS,and an animal model to simulate natu-ral MDS pathogenesis is urgently needed.Methods:In characterizing the genetically diverse mouse strains of the Collaborative Cross(CC)we observed that one,designated JUN,had abnormal hematological traits.This strain was thus further analyzed for phenotypic and pathological iden-tification,comparing the changes in each cell population in peripheral blood and in bone marrow.Results:In a specific-pathogen free environment,mice of the JUN strain are rela-tively thin,with healthy appearance.However,in a conventional environment,they become lethargic,develop wrinkled yellow hair,have loose and light stools,and are prone to infections.We found that the mice were cytopenic,which was due to abnor-mal differentiation of multipotent bone marrow progenitor cells.These are common characteristics of MDS.Conclusions:A mouse strain,JUN,was found displaying spontaneous myelodysplas-tic syndrome.This strain has the advantage over existing models in that it develops MDS spontaneously and is more similar to human MDS than genetically modified mouse models.JUN mice will be an important tool for pathogenesis research of MDS and for evaluation of new drugs and treatments.

关键词： myelodysplastic syndrome(MDS) spontaneous mouse model The Collaborative Cross Mice