Use In Preclinical Research Research Articles

First-in-Human Evaluation of [18F]FDOPA Produced by Organo-Photoredox Reactions.

Photoredox is a powerful synthetic tool in organic chemistry and has been widely used in various fields, including nuclear medicine and molecular imaging. In particular, acridinium-based organophotoredox radiolabeling has significantly impacted the production and discovery of positron emission tomography (PET) agents. Despite their extensive use in preclinical research, no PET agents synthesized by acridinium photoredox labeling have been tested in humans. [18F]FDOPA is clinically used for tumor diagnosis and the evaluation of neuropsychiatric disorders, but its application is limited by complex synthesis methods, the need for expensive modules, and/or the high cost of consumable materials/cassettes. In this report, we integrated a photoredox labeling unit with an automated module and produced [18F]FDOPA for human study. This research not only represents the first human study of a PET agent generated by acridinium-based organophotoredox reactions but also demonstrates the safety of this novel labeling method, serving as a milestone/reference for the clinical translation of other PET agents generated by this technique in the future.

An in vitro model to study immune activation, epithelial disruption and stromal remodelling in inflammatory bowel disease and fistulising Crohn's disease.

At present, preclinical models of inflammatory bowel disease (IBD) are insufficient, limiting translation between research and new therapeutics. This is especially true for fistulising Crohn's disease (CD), as the severe lack of relevant models hinders research progression. To address this, we present in vitro human IBD mucosal models that recapitulate multiple pathological hallmarks of IBD simultaneously in one model system - immune cell infiltration, stromal remodelling and epithelial disruption. Stimulation of models induces epithelial aberrations common in IBD tissue including altered morphology, microvilli abnormalities, claudin gene expression changes and increased permeability. Inflammatory biomarkers are also significantly increased including cytokines and chemokines integral to IBD pathogenesis. Evidence of extracellular matrix remodelling, including upregulated matrix-metalloproteinases and altered basement membrane components, suggests the models simulate pathological stromal remodelling events that closely resemble fistulising CD. Importantly, MMP-9 is the most abundant MMP and mimics the unique localisation observed in IBD tissue. The inflamed models were subsequently used to elucidate the involvement of TNF-α and IFN- γ in intestinal stromal remodelling, in which TNF-α but not IFN- γ induced MMP upregulation, specifically of MMP-3 and MMP-9. Collectively, our results demonstrate the potential of the IBD models for use in preclinical research in IBD, particularly for fistulising CD.

Probenecid, an Old Drug with Potential New Uses for Central Nervous System Disorders and Neuroinflammation.

Probenecid is an old uricosuric agent used in clinics to treat gout and reduce the renal excretion of antibiotics. In recent years, probenecid has gained attention due to its ability to interact with membrane proteins such as TRPV2 channels, organic anion transporters, and pannexin 1 hemichannels, which suggests new potential therapeutic utilities in medicine. Some current functions of probenecid include their use as an adjuvant to increase the bioavailability of several drugs in the Central Nervous System (CNS). Numerous studies also suggest that this drug has important neuroprotective, antiepileptic, and anti-inflammatory properties, as evidenced by their effect against neurological and neurodegenerative diseases. In these studies, the use of probenecid as a Panx1 hemichannel blocker to reduce neuroinflammation is highlighted since neuroinflammation is a major trigger for diverse CNS alterations. Although the clinical use of probenecid has declined over the years, advances in its use in preclinical research indicate that it may be useful to improve conventional therapies in the psychiatric field where the drugs used have a low bioavailability, either because of a deficient passage through the blood-brain barrier or a high efflux from the CNS or also a high urinary clearance. This review summarizes the history, pharmacological properties, and recent research uses of probenecid and discusses its future projections as a potential pharmacological strategy to intervene in neurodegeneration as an outcome of neuroinflammation.

Investigating Peripheral Regional Anesthesia Using Induced Pluripotent Stem Cell Technology: Exploring Novel Terrain.

Investigating Peripheral Regional Anesthesia Using Induced Pluripotent Stem Cell Technology: Exploring Novel Terrain.

Improved method for surgical induction of chronic hypertension in mice.

ABSTRACTChronic hypertension can be induced in mice by one-kidney one-clip (1K1C) or two-kidney one-clip surgery, transgenic overexpression of angiotensinogen and renin, administration of deoxycorticosterone acetate-salt, supplying Nitro-L-arginine methyl-ester in the drinking water and Angiotensin-II infusion. Although each model has its own pros and cons, selection of a model that mimics human hypertensive disease accurately is essential to ensure rigor and reproducibility in hypertension research. 1K1C mice represent an efficient, budget-friendly, and translationally capable model; however, their use in preclinical research has remained largely hindered due to concerns about potential technical complexity and lack of reported information regarding procedure-related mortality rates. Here, we describe in detail an improved version of the 1K1C surgery in mice that has zero intraoperative mortality and excellent survival rates in a long-term setting and permits the development of stable chronic hypertension and its target organ complications. Key to this outcome is unilateral nephrectomy 1 week after renal artery clipping to decelerate the blood pressure (BP) increase, which allows the organism to adapt better to the BP rise. The technical and animal welfare improvements presented here may promote the acceptance of the 1K1C model.

Lymphangion‐Chip Experimental Platform Supports Co‐culture and Signaling Between Lymphatic Endothelial and Mural Cells

The pathophysiology of several lymphatic diseases, such as lymphedema, depends on the function of lymphangions that drive lymph flow. Even though the signaling between two main cellular components of a lymphangion, Lymphatic Endothelial Cells (LECs) and Lymphatic Muscle Cells (LMCs), is responsible for crucial lymphatic functions, there are no in vitro models that have included both cell types in a physiologically relevant environment. Here, a fabrication technique (Gravitational Lumen Patterning or GLP) is developed to create Lymphangion‐Chip. This organ‐on‐chip consists of co‐culture of a monolayer of endothelial lumen surrounded by multiple and uniformly thick layers of muscle cells. The platform allows construction of a wide range of luminal diameters and muscular layer thicknesses, thus providing a toolbox to create variable anatomy. In this device, lymphatic muscle cells align circumferentially while endothelial cells aligned axially under flow, as only observed in vivo in the past. This model further demonstrated a robust sensitivity of this relative alignment of the two cells with respect to the presence or absence of co‐culture and mechanical forces (shear stress), thus suggesting that LECs and LMCs are biologically and functionally active within the chip. This system successfully characterizes the dynamics of cell size, density, growth, alignment, and intercellular gap due to co‐culture and shear. The time‐dependent decrease in the subendothelial gap strongly suggests proactive LEC‐LMC signaling as LECs and LMCs grow and proliferate within the device. Further exposure to pro‐inflammatory cytokines reveals that the device could produce the regulation of endothelial barrier function through the lymphatic muscle cells. Finally, measurement of intracellular calcium of LECs and LMCs while exposed to step and oscillatory flow profiles with various shear amplitudes revealed the bidirectional mechanism of calcium signaling within lymphatic vessel. Therefore, this organ‐chip technology allows researchers to include essential lymphatic vascular components in a tunable 3D microphysiological system that is suitable for use in preclinical research of lymphatic and blood mechanobiology, inflammation, and translational outcomes.

Abstract 378: Lymphangion-chip: It Recreates Intercellular Signaling Between Lymphatic Vascular Endothelial And Mural Cells In Health And Disease

The pathophysiology of several lymphatic diseases, such as lymphedema, depends on the function of lymphangions. Even though the signaling between two main cellular components of a lymphangion, Lymphatic Endothelial Cells (LECs) and Lymphatic Muscle Cells (LMCs), is responsible for crucial functions, there are no in vitro models that have included both cell types in a physiologically relevant environment. Here, a fabrication technique is developed to create a Lymphangion-Chip. This organ-on-chip consists of co-culture of a monolayer of endothelial lumen surrounded by multiple and uniformly thick layers of muscle cells. The platform allows construction of a wide range of luminal diameters and muscular layer thicknesses, thus providing a toolbox to create variable anatomy. In this device, the muscle cells align circumferentially while endothelial cells aligned axially under flow, as only observed in vivo in the past. This model further demonstrated a robust sensitivity of this relative alignment of the two cells as well as dynamics of cell size, density, growth, and intercellular gap with respect to the presence or absence of co-culture and mechanical forces (shear). The time-dependent decrease in the subendothelial gap strongly suggests proactive LEC-LMC signaling as LECs and LMCs grow and proliferate within the device. Further exposure to pro-inflammatory cytokines reveals that the device could produce the regulation of endothelial barrier function through the muscle cells. Finally, measurement of intracellular calcium of LECs and LMCs while exposed to step and oscillatory flow profiles with various shear amplitudes revealed the bidirectional mechanism of calcium signaling within the platform. Therefore, this technology allows researchers to include essential lymphatic vascular components in a tunable 3D microphysiological system that is suitable for use in preclinical research of lymphatic mechanobiology, inflammation, and translational outcomes.

A novel, simplified, and reproducible porcine model of acute ischemic liver failure with portal vein preservation.

The current ischemic models of liver failure are difficult and usually time-consuming to produce. The aim of this study was to develop a simplified and reproducible porcine model of acute liver failure for use in preclinical research. Eighteen Bama miniature pigs were randomly divided into Groups A, B, and C. The hepatic artery and common bile duct were ligated in all groups. While the portal vein was completely preserved in Group A, it was narrowed by 1/3 and 1/2 in Groups B and C, respectively. Results of biochemical analyses, encephalopathy scores, and survival times were compared among the groups. Results of hematoxylin-eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Masson staining, and Ki-67 analyses were recorded. Survival times in Groups B and C were 11.67 ± 1.86 and 2.16 ± 0.75 days, respectively, shorter than that in Group A (>15 days). Following surgery, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, total bilirubin, and direct bilirubin levels significantly increased relative to baseline values in all groups (P<0.05). Groups B and C exhibited a significant decrease in encephalopathy scores and a significant increase in ammonia levels, which were negatively correlated with one another. Pathological analysis revealed obvious necrosis of liver cells, which correlated closely with the degree of portal vein constriction. Our simple, highly reproducible model effectively mimics the clinical characteristics of acute liver failure in humans and provides a foundation for further research on artificial liver support system development.

High-dimensional single cell mass cytometry analysis of the murine hematopoietic system reveals signatures induced by ageing and physiological pathogen challenges

BackgroundImmune ageing is a result of repetitive microbial challenges along with cell intrinsic or systemic changes occurring during ageing. Mice under ‘specific-pathogen-free’ (SPF) conditions are frequently used to assess immune ageing in long-term experiments. However, physiological pathogenic challenges are reduced in SPF mice. The question arises to what extent murine experiments performed under SPF conditions are suited to analyze immune ageing in mice and serve as models for human immune ageing. Our previous comparisons of same aged mice with different microbial exposures, unambiguously identified distinct clusters of immune cells characteristic for numerous previous pathogen encounters in particular in pet shop mice.ResultsWe here performed single cell mass cytometry assessing splenic as secondary and bone marrow as primary lymphoid organ-derived leukocytes isolated from young versus aged SPF mice in order to delineate alterations of the murine hematopoietic system induced during ageing. We then compared immune clusters from young and aged SPF mice to pet shop mice in order to delineate alterations of the murine hematopoietic system induced by physiological pathogenic challenges and those caused by cell intrinsic or systemic changes during ageing. Notably, distinct immune signatures were similarly altered in both pet shop and aged SPF mice in comparison to young SPF mice, including increased frequencies of memory T lymphocytes, effector-cytokine producing T cells, plasma cells and mature NK cells. However, elevated frequencies of CD4+ T cells, total NK cells, granulocytes, pDCs, cDCs and decreased frequencies of naïve B cells were specifically identified only in pet shop mice. In aged SPF mice specifically the frequencies of splenic IgM+ plasma cells, CD8+ T cells and CD4+ CD25+ Treg were increased as compared to pet shop mice and young mice.ConclusionsOur study dissects firstly how ageing impacts both innate and adaptive immune cells in primary and secondary lymphoid organs. Secondly, it partly distinguishes murine intrinsic immune ageing alterations from those induced by physiological pathogen challenges highlighting the importance of designing mouse models for their use in preclinical research including vaccines and immunotherapies.

Metabolic, Phenotypic, and Neuropathological Characterization of the Tg4-42 Mouse Model for Alzheimer's Disease.

Background:Preclinical Alzheimer’s disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research. Furthermore, metabolic biomarkers which have the potential to detect biochemical changes, are crucial to gain deeper insights into the pathways, the underlying pathological mechanisms and disease progression.Objective:We thus performed an in-depth characterization of Tg4-42 mice by using an integrated approach to analyze alterations of complex biological networks in this AD in vivo model.Methods:Therefore, untargeted NMR-based metabolomic phenotyping was combined with behavioral tests and immunohistological and biochemical analyses.Results:Our in vivo experiments demonstrate a loss of body weight increase in homozygous Tg4-42 mice over time as well as severe impaired learning behavior and memory deficits in the Morris water maze behavioral test. Furthermore, we found significantly altered metabolites in two different brain regions and metabolic changes of the glutamate/4-aminobutyrate-glutamine axis. Based on these results, downstream effects were analyzed showing increased Aβ42 levels, increased neuroinflammation as indicated by increased astro- and microgliosis as well as neuronal degeneration and neuronal loss in homozygous Tg4-42 mice.Conclusion:Our study provides a comprehensive characterization of the Tg4-42 mouse model which could lead to a deeper understanding of pathological features of AD. Additionally this study reveals changes in metabolic biomarker which set the base for future preclinical studies or drug development.

The \u201ccompletely randomised\u201d and the \u201crandomised block\u201d are the only experimental designs suitable for widespread use in pre-clinical research

Too many pre-clinical experiments are giving results which cannot be reproduced. This may be because the experiments are incorrectly designed. In “Completely randomized” (CR) and “Randomised block” (RB) experimental designs, both the assignment of treatments to experimental subjects and the order in which the experiment is done, are randomly determined. These designs have been used successfully in agricultural and industrial research and in clinical trials for nearly a century without excessive levels of irreproducibility. They must also be used in pre-clinical research if the excessive level of irreproducibility is to be eliminated. A survey of 100 papers involving mice and rats was used to determine whether scientists had used the CR or RB designs. The papers were assigned to three categories “Design acceptable”, “Randomised to treatment groups”, so of doubtful validity, or “Room for improvement”. Only 32 ± 4.7% of the papers fell into the first group, although none of them actually named either the CR or RB design. If the current high level of irreproducibility is to be eliminated, it is essential that scientists engaged in pre-clinical research use “Completely randomised” (CR), “Randomised block” (RB), or one of the more specialised named experimental designs described in textbooks on the subject.

Behavioral Teleporting of Individual Ethograms onto Inanimate Robots: Experiments on Social Interactions in Live Zebrafish.

SummarySocial behavior is widespread in the animal kingdom, and it remarkably influences human personal and professional lives. However, a thorough understanding of the mechanisms underlying social behavior is elusive. Integrating the seemingly different fields of robotics and preclinical research could bring new insight on social behavior. Toward this aim, we established “behavioral teleporting” as an experimental solution to independently manipulate multiple factors underpinning social interactions. Behavioral teleporting consists of real-time transfer of the complete ethogram of a live zebrafish onto a remotely-located robotic replica. Through parallel and simultaneous behavioral teleporting, we studied the interaction between two live fish swimming in remotely-located tanks: each live fish interacted with an inanimate robot that mirrored the behavior of the other fish, and the morphology of each robot was independently tailored. Our results indicate that behavioral teleporting can preserve natural interaction between two live animals, while allowing fine control over morphological features that modulate social behavior.

P5005Diagnostic and prognostic utilities of insulin-like growth factor-binding protein-7 in patients presenting to the emergency department with dyspnea: results from the ICON-RELOADED study

Abstract Background Increased activity of insulin-like growth factor–binding protein-7 (IGFBP7) is associated with cellular senescence, tissue aging, and obesity. Prior studies in chronic heart failure (HF) have linked IGFBP7 to impaired myocardial relaxation. The role of IGFBP7 measurement in acute HF remains unclear. Purpose To examine whether concentrations of IGFBP7 in patients presenting with dyspnea to the emergency department (ED) will aid in the diagnosis and prognosis of acute HF beyond N-terminal pro- B type natriuretic peptide (NT-proBNP). Methods The ICON-RELOADED (International Collaborative of NT-proBNP- Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) study was a prospective, multicenter clinical trial conducted at 19 sites in North America that enrolled subjects ≥22 years of age presenting to ED with complaints of dyspnea. Subjects were blindly adjudicated for the diagnosis of acute HF. A blood sample was taken at enrollment. Six-month prognosis for death/repeat hospitalization was obtained. IGFBP7 was measured using a pre-clinical research use only assay. Results Among 1449 patients (n=274 with acute HF), those with IGFBP7 concentrations in the highest quartile (&gt;123.7 ng/mL) were older, more likely to be male and to have a history of hypertension and HF (all p&lt;0.001). They also had lower estimated glomerular filtration rate (eGFR) and the lowest left ventricular ejection fraction (41% ± 21%) prior to study enrollment (all p&lt;0.001). Independent predictors of IGFBP7 included age, male sex, history of diabetes, history of HF, and eGFR (all p&lt;0.001). Median concentrations of NT-proBNP (2844 vs. 99 ng/mL) and IGFBP7 (146.1 vs. 86.1 ng/mL) were significantly higher in those with acute HF (both p&lt;0.001); addition of IGFBP7 to NT-proBNP concentrations improved discrimination, increasing the area under the receiver operating curve for diagnosis of acute HF (from 0.91 to 0.94; p&lt;0.001) (Figure 1). Addition of IGFBP7 to a complete model of independent predictors of acute HF (including NT-proBNP) improved model calibration; IGFBP7 also significantly re-classified acute HF diagnosis beyond NT-proBNP alone (net reclassification improvement +0.25; p&lt;0.001). Higher log2-IGFBP7 concentrations predicted death/rehospitalization at 6 months (hazard ratio 1.74 per log2-standard deviation, 95% confidence interval 1.26–2.40, p=0.001). In Kaplan-Meier analyses, supramedian concentrations of IGFBP7 were associated with shorter event-free survival (log-rank p&lt;0.001). ROC curve for diagnosis of acute HF Conclusions Among patients with acute dyspnea, concentrations of IGFBP7 add to NT-proBNP for diagnosis of acute HF and provide added prognostic utility for short-term risk. Acknowledgement/Funding Funding for this study was provided by Roche Diagnostics (Risch-Rotkreuz, Switzerland).

Experimental non-alcoholic steatohepatitis in G\xf6ttingen Minipigs: consequences of high fat-fructose-cholesterol diet and diabetes

BackgroundNon-alcoholic fatty liver disease (NAFLD) is the most common liver disease in humans, and ranges from steatosis to non-alcoholic steatohepatitis (NASH), the latter with risk of progression to cirrhosis. The Göttingen Minipig has been used in studies of obesity and diabetes, but liver changes have not been described. The aim of this study was to characterize hepatic changes in Göttingen Minipigs with or without diabetes, fed a diet high in fat, fructose, and cholesterol to see if liver alterations resemble features of human NAFLD/NASH.MethodsFifty-four male castrated minipigs (age 6 to 7 months) were distributed into four groups and diet-fed for 13 months. Groups were: lean controls fed standard diet (SD, n = 8), a group fed high fat/fructose/cholesterol diet (FFC, n = 16), a group fed high fat/fructose/cholesterol diet but changed to standard diet after 7 months (diet normalization, FFC/SD, n = 16), and a streptozotocin-induced diabetic group fed high fat/fructose/cholesterol diet (FFCDIA, n = 14). At termination, blood samples for analyses of circulating biomarkers and liver tissue for histopathological assessment and analyses of lipids and glycogen content were collected.ResultsIn comparison with SD and FFC/SD, FFC and FFCDIA pigs developed hepatomegaly with increased content of cholesterol, whereas no difference in triglyceride content was found. FFC and FFCDIA groups had increased values of circulating total cholesterol and triglycerides and the hepatic circulating markers alkaline phosphatase and glutamate dehydrogenase. In the histopathological evaluation, fibrosis (mainly located periportally) and inflammation along with cytoplasmic alterations (characterized by hepatocytes with pale, granulated cytoplasm) were found in FFC and FFCDIA groups compared to SD and FFC/SD. Interestingly, FFC/SD also had fibrosis, a feature not seen in SD. Only two FFC and three FFCDIA pigs had > 5% steatosis, and no hepatocellular ballooning or Mallory–Denk bodies were found in any of the pigs.ConclusionsFibrosis, inflammation and cytoplasmic alterations were characteristic features in the livers of FCC and FFCDIA pigs. Overall, diabetes did not exacerbate the hepatic changes compared to FFC. The limited presence of the key human-relevant pathological hepatic findings of steatosis and hepatocellular ballooning and the variation in the model, limits its use in preclinical research without further optimisation.

Toxicity assays using expanded liver cells promote the reduction of animal use in pre-clinical research

We will devote a considerable amount of time in this course to developing explicit, implicit, numerical, and graphical solutions of differential equations. In this chapter we discuss first order ordinary differential equations and some methods used to construct explicit, implicit, numerical, and graphical solutions of them. Several of the equations and methods of solution discussed here will be used in later chapters of the text.

Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL−G−F mice before prominent plaque deposition

Amyloid-β (Aβ) peptides occur in the brains of patients with Alzheimer’s disease (AD), but their role in functional impairment is still debated. High levels of APP and APP fragments in mice that overexpress APP might confound their use in preclinical research. We examined the occurrence of behavioral, cognitive and neuroimaging changes in APPNL−G−F knock-in mice that display Aβ42 amyloidosis in the absence of APP overexpression. Female APPNL−G−F mice (carrying Swedish, Iberian and Arctic APP mutations) were compared to APPNL mice (APP Swedish) at 3, 7 and 10 months. Mice were subjected to a test battery that referred to clinical AD symptoms, comprising cage activity, open field, elevated plus maze, social preference and novelty test, and spatial learning, reversal learning and spatial reference memory performance. Our assessment confirmed that behavior at these early ages was largely unaffected in these mice in accordance with previous reports, with some subtle behavioral changes, mainly in social and anxiety-related test performance. Resting-state functional MRI (rsfMRI) assessed connectivity between hippocampal and prefrontal regions with an established role in flexibility, learning and memory. Increased prefrontal-hippocampal network synchronicity was found in 3-month-old APPNL−G−F mice. These functional changes occurred before prominent amyloid plaque deposition.

The ethics of genome editing in the clinic: A dose of realism for healthcare leaders.

Genome editing technologies promise therapeutic advances for genetic diseases. We discuss the ethical and societal issues raised by these technologies, including their use in preclinical research, their potential to address mutations in somatic cells, and their potential to make germ line alterations that may be passed to subsequent generations. We call for a proportionate response from health leaders based on a realistic assessment of benefits, risks, and timelines for clinical translation.

Introduction to special issue on animal models of neuropsychiatric disorders and substance use disorders: Progress and gaps.

This is an introduction to the special issue, "Animal Models of Neuropsychiatric Disorders and Substance Use Disorders: Progress and Gaps." This issue presents 6 original research reports describing the use of mice and rats to model neurodevelopmental disorders, depressive disorders, anxiety disorders, and substance use disorders. Collectively, these studies demonstrate the progress of the field and the gaps and challenges that remain. They also illustrate the range of conditions that are informed by animal models and identify the clinical populations that stand to benefit from their use in preclinical research. (PsycINFO Database Record

The Potential of Adaptive Design in Animal Studies.

Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data on the safety and effectiveness of prospective treatments. These studies can be costly and time consuming, and may also raise concerns about the ethical treatment of animals when potentially harmful procedures are involved. Adaptive design is a process by which the methods used in a study may be altered while it is being conducted in response to preliminary data or other new information. Adaptive design has been shown to be useful in reducing the time and costs associated with clinical trials, and may provide similar benefits in preclinical animal studies. The purpose of this review is to summarize various aspects of adaptive design and evaluate its potential for use in preclinical research.

Generation of Naive Induced Pluripotent Stem Cells from Rhesus Monkey Fibroblasts

Conventional embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) derived from primates resemble mouse epiblast stem cells, raising an intriguing question regarding whether the naive pluripotent state resembling mouse embryonic stem cells (mESCs) exists in primates and how to capture it invitro. Here we identified several specific signaling modulators that are sufficient to generate rhesus monkey fibroblast-derived iPSCs with the features of naive pluripotency in terms of growth properties, gene expression profiles, self-renewal signaling, X-reactivation, and the potential to generate cross-species chimeric embryos. Interestingly, together with recent reports of naive human pluripotent stem cells, our findings suggest several conserved signaling pathways shared with rodents and specific to primates, providing significant insights for acquiring naive pluripotency from other species. In addition, the derivation of rhesus monkey naive iPSCs also provides a valuable cell source for use in preclinical research and disease modeling.