Increased hyaluronan by naked mole-rat HAS2 extends healthspan in mice
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PROVIDER: PRJNA980211 | ENA |
REPOSITORIES: ENA
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Project description:Abundant high molecular weight hyaluronic acid (HMW-HA) contributes to cancer resistance and possibly longevity of the longest-lived rodent, the naked mole-rat1,2. To study whether the benefits of increased HMW-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHAS2). nmrHAS2 mice showed increase in hyaluronan levels in several tissues, and lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHAS2 mice shifted towards that of longer-lived species. The most striking change observed in nmrHAS2 mice was attenuated inflammation across multiple tissues. HMW-HA reduced inflammation via several pathways including direct immunoregulatory effect on immune cells, protection from oxidative stress, and improved gut barrier function during aging. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exploited to other species, and open new avenues for using HMW-HA to improve lifespan and healthspan
2023-09-08 | GSE234154 | GEO
Project description:Abundant high molecular weight hyaluronic acid (HMW-HA) contributes to cancer resistance and possibly longevity of the longest-lived rodent, the naked mole-rat1,2. To study whether the benefits of increased HMW-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHAS2). nmrHAS2 mice showed increase in hyaluronan levels in several tissues, and lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHAS2 mice shifted towards that of longer-lived species. The most striking change observed in nmrHAS2 mice was attenuated inflammation across multiple tissues. HMW-HA reduced inflammation via several pathways including direct immunoregulatory effect on immune cells, protection from oxidative stress, and improved gut barrier function during aging. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exploited to other species, and open new avenues for using HMW-HA to improve lifespan and healthspan.
2023-08-10 | GSE234563 | GEO
Project description:Increased hyaluronan by naked mole-rat HAS2 extends healthspan in mice
| PRJNA982056 | ENA
Project description:Abundant high molecular weight hyaluronic acid (HMW-HA) contributes to cancer resistance and possibly longevity of the longest-lived rodent, the naked mole-rat1,2. To study whether the benefits of increased HMW-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHAS2). nmrHAS2 mice showed increase in hyaluronan levels in several tissues, and lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHAS2 mice shifted towards that of longer-lived species. The most striking change observed in nmrHAS2 mice was attenuated inflammation across multiple tissues. HMW-HA reduced inflammation via several pathways including direct immunoregulatory effect on immune cells, protection from oxidative stress, and improved gut barrier function during aging. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exploited to other species, and open new avenues for using HMW-HA to improve lifespan and healthspan.
2023-06-12 | GSE234286 | GEO
Project description:Increased hyaluronan by naked mole-rat HAS2 improves healthspan in mice [microbiome]
| PRJNA980694 | ENA
Project description:Background: The extracellular matrix provides organizational context for solid organs. During disease, such as acute myocardial infarction, the composition of the extracellular matrix changes remarkably. One of the most notable changes in the extracellular matrix is in the accumulation of collagen; however, hyaluronan rivals collagen in terms of its abundance. Yet, the extent to which specific cells and enzymes may contribute to such accumulation has been largely unexplored. Here, we hypothesized that activated cardiac fibroblasts produce hyaluronan via hyaluronan synthase 2 (HAS2). Methods and Results: Using immunofluorescence, biochemical extraction, and ELISA, we show that hyaluronan accumulates following myocardial infarction and persists through at least four weeks. Our analyses of failing heart RNA sequencing data suggest fibroblasts are the cells most changed in expression of HAS2. Given these insights, we used HAS2 gain- and loss-of-function approaches to examine the extent to which activated cardiac fibroblasts produced hyaluronan. TGF-induced activation of fibroblasts caused a significant increase in Has2 mRNA and concomitant accumulation of hyaluronan greater than 1 MDa in size. Deletion of Has2 abrogated TGF-induced production of hyaluronan. In addition, overexpression of Has2 was sufficient to cause an increase in hyaluronan accumulation in the absence of TGF-induced activation. Given the magnitude of hyaluronan production, and that hyaluronan has been reported to have biologic activity, we then queried whether the primary functions of fibroblasts (proliferation, migration, and collagen production) were impacted by hyaluronan treatment. Our data indicated negligible impacts of Has2 on proliferation, migration, and collagen production. Exposing fibroblasts to exogenous hyaluronan also had minimal impact on fibroblasts. We also assessed whether fibroblast-borne Hyal2 plays a role in degradation of hyaluronan, and our data indicated little impact of Hyal2 on hyaluronan accumulation (or even any impacts on the transcriptional profile of fibroblasts). Conclusion: Activated fibroblasts produce high molecular weight hyaluronan, and the production of hyaluronan depends on Has2. The robust production of hyaluronan by fibroblasts does not appear to impact fibroblast function.
2026-01-30 | GSE284092 | GEO
Project description:Background: The extracellular matrix provides organizational context for solid organs. During disease, such as acute myocardial infarction, the composition of the extracellular matrix changes remarkably. One of the most notable changes in the extracellular matrix is in the accumulation of collagen; however, hyaluronan rivals collagen in terms of its abundance. Yet, the extent to which specific cells and enzymes may contribute to such accumulation has been largely unexplored. Here, we hypothesized that activated cardiac fibroblasts produce hyaluronan via hyaluronan synthase 2 (HAS2). Methods and Results: Using immunofluorescence, biochemical extraction, and ELISA, we show that hyaluronan accumulates following myocardial infarction and persists through at least four weeks. Our analyses of failing heart RNA sequencing data suggest fibroblasts are the cells most changed in expression of HAS2. Given these insights, we used HAS2 gain- and loss-of-function approaches to examine the extent to which activated cardiac fibroblasts produced hyaluronan. TGF-induced activation of fibroblasts caused a significant increase in Has2 mRNA and concomitant accumulation of hyaluronan greater than 1 MDa in size. Deletion of Has2 abrogated TGF-induced production of hyaluronan. In addition, overexpression of Has2 was sufficient to cause an increase in hyaluronan accumulation in the absence of TGF-induced activation. Given the magnitude of hyaluronan production, and that hyaluronan has been reported to have biologic activity, we then queried whether the primary functions of fibroblasts (proliferation, migration, and collagen production) were impacted by hyaluronan treatment. Our data indicated negligible impacts of Has2 on proliferation, migration, and collagen production. Exposing fibroblasts to exogenous hyaluronan also had minimal impact on fibroblasts. We also assessed whether fibroblast-borne Hyal2 plays a role in degradation of hyaluronan, and our data indicated little impact of Hyal2 on hyaluronan accumulation (or even any impacts on the transcriptional profile of fibroblasts). Conclusion: Activated fibroblasts produce high molecular weight hyaluronan, and the production of hyaluronan depends on Has2. The robust production of hyaluronan by fibroblasts does not appear to impact fibroblast function.
2026-01-30 | GSE284157 | GEO
Project description:Background: The extracellular matrix provides organizational context for solid organs. During disease, such as acute myocardial infarction, the composition of the extracellular matrix changes remarkably. One of the most notable changes in the extracellular matrix is in the accumulation of collagen; however, hyaluronan rivals collagen in terms of its abundance. Yet, the extent to which specific cells and enzymes may contribute to such accumulation has been largely unexplored. Here, we hypothesized that activated cardiac fibroblasts produce hyaluronan via hyaluronan synthase 2 (HAS2). Methods and Results: Using immunofluorescence, biochemical extraction, and ELISA, we show that hyaluronan accumulates following myocardial infarction and persists through at least four weeks. Our analyses of failing heart RNA sequencing data suggest fibroblasts are the cells most changed in expression of HAS2. Given these insights, we used HAS2 gain- and loss-of-function approaches to examine the extent to which activated cardiac fibroblasts produced hyaluronan. TGF-induced activation of fibroblasts caused a significant increase in Has2 mRNA and concomitant accumulation of hyaluronan greater than 1 MDa in size. Deletion of Has2 abrogated TGF-induced production of hyaluronan. In addition, overexpression of Has2 was sufficient to cause an increase in hyaluronan accumulation in the absence of TGF-induced activation. Given the magnitude of hyaluronan production, and that hyaluronan has been reported to have biologic activity, we then queried whether the primary functions of fibroblasts (proliferation, migration, and collagen production) were impacted by hyaluronan treatment. Our data indicated negligible impacts of Has2 on proliferation, migration, and collagen production. Exposing fibroblasts to exogenous hyaluronan also had minimal impact on fibroblasts. We also assessed whether fibroblast-borne Hyal2 plays a role in degradation of hyaluronan, and our data indicated little impact of Hyal2 on hyaluronan accumulation (or even any impacts on the transcriptional profile of fibroblasts). Conclusion: Activated fibroblasts produce high molecular weight hyaluronan, and the production of hyaluronan depends on Has2. The robust production of hyaluronan by fibroblasts does not appear to impact fibroblast function.
2026-01-30 | GSE284546 | GEO
Project description:The naked mole-rat (NMR), Heterocephalus glaber, is a mouse-sized subterranean rodent native to East Africa. Research on NMRs is intensifying in an effort to gain leverage from their unusual physiology, long-life span and cancer resistance for the development of new theraputics. Few studies have attempted to explain the reasons behind the NMR’s cancer resistance, but most prominently Tian et al. reported that NMR cells produce high-molecular weight hyaluronan as a potential cause for the NMR’s cancer resistance. Tian et al. have shown that NMR cells are resistant to transformation by SV40 Large T Antigen (SV40LT) and oncogenic HRAS (HRASG12V), a combination of oncogenes sufficient to transform mouse and rat fibroblasts. We have developed a number of lentiviral vectors to deliver both these oncogenes and generated 106 different cell lines from five different tissues and eleven different NMRs, and report here that contrary to Tian et al.’s observation, NMR cells are susceptible to oncogenic transformation by SV40LT and HRASG12V. Our data thus point to a non-cell autonomous mechanism underlying the remarkable cancer resistance of NMRs. Identifying these non-cell autonomous mechanisms could have significant implications on our understanding of human cancer development.
2020-06-12 | E-MTAB-8932 | biostudies-arrayexpress
Project description:Background: HAS2 is a member of the gene family encoding hyaluronan synthase 2 (HAS2) which can generate high molecular weight hyaluronan (HMW-HA). Although we previously reported that HAS2 is a novel candidate gene for susceptibility to adult asthma., little is known about whether HAS2 dysfunction affect eosinophilic airway inflammation. Objective: We therefore hypothesized that attenuation of HAS2 will enhance eosinophilic airway inflammation. Methods: C57BL/6 wild type (WT) mice, Has2 heterozygous deficient (Has2+/−) mice were used in eosinophilic airway inflammation model which induced by ovalbumin (OVA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to detect Has2 and HA binding protein mRNA expression levels. Lung tissue and lavage fluid (BALF) were analyzed for inflammation and various cytokines and chemokines. Airway resistance was measured using forced oscillation technique. gene expression analyses were also performed to elucidate further pathogenesis. Results: The expression levels of Has2 mRNA was significantly decreased in OVA stimulated Has2+/− (Has2+/−-OVA) mice. Has2+/−-OVA mice also displayed significant reduce of CD44, and TGF-beta1 mRNA expression. BALF eosinophil number, levels of various Th2 cytokines and chemokines in BALF, and airway responsiveness were significantly increased in Has2+/−-OVA mice compared with similarly treated WT mice. ILK Signaling and PKA signaling were downregulated significantly more in Has2+/−-OVA mice compared with similarly treated WT mice. Conclusions: Has2 dysfunction induce more intense allergic eosinophilic airway inflammation and increase of airway hyper responsiveness with impairment of HAS2-CD44-TGF-beta signaling. Modulating HAS2 signaling might provide novel therapeutic targets for intractable bronchial asthma patients.
2022-04-04 | GSE148161 | GEO