Effect of aging on stem cells.
Ahmed Abu Shufian Ishtiaq,Sheng Matilda Hc,Wasnik Samiksha,Baylink David J,Lau Kin-Hing William
World journal of experimental medicine
Pluripotent stem cells have the remarkable self-renewal ability and are capable of differentiating into multiple diverse cells. There is increasing evidence that the aging process can have adverse effects on stem cells. As stem cells age, their renewal ability deteriorates and their ability to differentiate into the various cell types is altered. Accordingly, it is suggested aging-induced deterioration of stem cell functions may play a key role in the pathophysiology of the various aging-associated disorders. Understanding the role of the aging process in deterioration of stem cell function is crucial, not only in understanding the pathophysiology of aging-associated disorders, but also in future development of novel effective stem cell-based therapies to treat aging-associated diseases. This review article first focuses on the basis of the various aging disease-related stem cell dysfunction. It then addresses the several concepts on the potential mechanism that causes aging-related stem cell dysfunction. It also briefly discusses the current potential therapies under development for aging-associated stem cell defects.
10.5493/wjem.v7.i1.1
Treating Age-Related Diseases with Somatic Stem Cells.
Brooks Robert W,Robbins Paul D
Advances in experimental medicine and biology
Life expectancy in the developed world has advanced beyond the number of years in which healthy tissue homeostasis can be maintained, and as a result, the number of persons with severe and debilitating chronic illnesses, including cancer, diabetes, osteoarthritis, osteoporosis, neurodegenerative and cardiovascular disease has continued to rise. One of the key underlying causes for the loss in the ability to replenish damaged tissues is the qualitative and quantitative decline in somatic stem cell populations. A concerted effort to understand why aging adult stem cells fail to maintain "stem" potential while simultaneously developing new strategies and therapeutic interventions to prevent or reverse age-dependent stem cell decline is required to improve the overall healthspan of our rapidly aging population. This review focuses on what drives stem cell dysfunction with age, the contribution of stem cell dysfunction in driving aging and therapeutic approaches using stem cells to treat aging.
10.1007/978-3-319-74470-4_3
Epigenetic Regulation of Mesenchymal Stem Cell Homeostasis.
Sui Bing-Dong,Zheng Chen-Xi,Li Meng,Jin Yan,Hu Cheng-Hu
Trends in cell biology
Mesenchymal stem cells (MSCs) have putative roles in maintaining adult tissue health, and the functional decline of MSCs has emerged as a crucial pathophysiological driver of various diseases. Epigenetic regulation is essential for establishing and preserving MSC homeostasis in vivo. Furthermore, growing evidence suggests that epigenetic dysregulation contributes to age- and disease-associated MSC alterations. Epigenetic marks in MSCs can be amplified through self-renewal divisions and transmitted to differentiated progeny, further perpetuating their role in tissue maintenance and pathogenesis. We review the epigenetic regulation of MSC homeostasis, emphasizing its contributions to organismal health and disease. Understanding these epigenetic mechanisms could hold promise as targets for MSC-mediated regenerative therapies.
10.1016/j.tcb.2019.11.006
Senescent Mesenchymal Stem Cells in Myelodysplastic Syndrome: Functional Alterations, Molecular Mechanisms, and Therapeutic Strategies.
Chen Xiaofang,Li Ningyu,Weng Jianyu,Du Xin
Frontiers in cell and developmental biology
Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic disorders related to hematopoietic stem and progenitor cell dysfunction. However, therapies that are currently used to target hematopoietic stem cells are not effective. These therapies are able to slow the evolution toward acute myeloid leukemia but cannot eradicate the disease. Mesenchymal stem cells (MSCs) have been identified as one of the main cellular components of the bone marrow microenvironment, which plays an indispensable role in normal hematopoiesis. When functional and regenerative capacities of aging MSCs are diminished, some enter replicative senescence, which promotes inflammation and disease progression. Recent studies that investigated the contribution of bone marrow microenvironment and MSCs to the initiation and progression of the disease have offered new insights into the MDS. This review presents the latest updates on the role of MSCs in the MDS and discusses potential targets for the treatment of MDS.
10.3389/fcell.2020.617466
Epigenetic Regulation of Bone Marrow Stem Cell Aging: Revealing Epigenetic Signatures associated with Hematopoietic and Mesenchymal Stem Cell Aging.
Cakouros Dimitrios,Gronthos Stan
Aging and disease
In this review we explore the importance of epigenetics as a contributing factor for aging adult stem cells. We summarize the latest findings of epigenetic factors deregulated as adult stem cells age and the consequence on stem cell self-renewal and differentiation, with a focus on adult stem cells in the bone marrow. With the latest whole genome bisulphite sequencing and chromatin immunoprecipitations we are able to decipher an emerging pattern common for adult stem cells in the bone marrow niche and how this might correlate to epigenetic enzymes deregulated during aging. We begin by briefly discussing the initial observations in yeast, drosophila and Caenorhabditis elegans () that led to the breakthrough research that identified the role of epigenetic changes associated with lifespan and aging. We then focus on adult stem cells, specifically in the bone marrow, which lends strong support for the deregulation of DNA methyltransferases, histone deacetylases, acetylates, methyltransferases and demethylases in aging stem cells, and how their corresponding epigenetic modifications influence gene expression and the aging phenotype. Given the reversible nature of epigenetic modifications we envisage "epi" targeted therapy as a means to reprogram aged stem cells into their younger counterparts.
10.14336/AD.2017.1213
Prospect of mesenchymal stem cells in therapy of osteoporosis: A review.
Aghebati-Maleki Leili,Dolati Sanam,Zandi Reza,Fotouhi Ali,Ahmadi Majid,Aghebati Ali,Nouri Mohammad,Kazem Shakouri Seyed,Yousefi Mehdi
Journal of cellular physiology
Osteoporosis is a systemic skeletal disease associated with reduced bone strong point that results in raised fracture risk, with decreased bone strength, leading to reduced bone mineral density and poor bone quality. It is the most common in older females but some men are also at high risk. Although considered as a predictable result of aging, it is can be avoidable and treatable. The existing treatment of osteoporosis mainly contains antiresorptive and anabolic agents. In spite of these improvements, concerns around unusual side-effects of antiresorptive drugs, and the lack of perfect confirmation in maintenance of their long-standing effectiveness is bring about many patients not receiving these drugs. Over the years, the stem cell-based therapy has attained substantial clinical consideration because of its potential to treat numerous diseases. The stem cell therapy has been recommended as a probable therapeutic approach for patients with osteoporosis. Even though the concept of stem cell-based therapy for osteoporosis has caught substantial attention, no clinical trial has been published on humans. The cell studies based on osteoporosis are primarily focused on osteoclastic activity and bone resorption procedures. Earlier, it was on osteoblastogenesis and in recent times, on the differentiation probable of mesenchymal stem cells. In this review, we have summarized the therapeutic role of stem cell-based strategy in osteoporosis.
10.1002/jcp.27833
Osteogenesis and aging: lessons from mesenchymal stem cells.
Infante Arantza,Rodríguez Clara I
Stem cell research & therapy
Aging is a high risk factor for the development of osteoporosis, a multifactorial age-related progressive disease characterized by reduced bone mass and increased risk of fractures. At the cellular level, the mesenchymal stem cell pool in the bone marrow niche shows a biased differentiation into adipogenesis at the cost of osteogenesis. This differentiation shift leads to decreased bone formation, contributing to the etiology of osteoporosis. This review will focus on the most recent/relevant molecular findings driving this functional impairment of mesenchymal stem cells in the aging process.
10.1186/s13287-018-0995-x
A crucial role for adipose tissue p53 in the regulation of insulin resistance.
Minamino Tohru,Orimo Masayuki,Shimizu Ippei,Kunieda Takeshige,Yokoyama Masataka,Ito Takashi,Nojima Aika,Nabetani Akira,Oike Yuichi,Matsubara Hisahiro,Ishikawa Fuyuki,Komuro Issei
Nature medicine
Various stimuli, such as telomere dysfunction and oxidative stress, can induce irreversible cell growth arrest, which is termed 'cellular senescence'. This response is controlled by tumor suppressor proteins such as p53 and pRb. There is also evidence that senescent cells promote changes related to aging or age-related diseases. Here we show that p53 expression in adipose tissue is crucially involved in the development of insulin resistance, which underlies age-related cardiovascular and metabolic disorders. We found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes-like disease and promoted senescence-like changes, such as increased activity of senescence-associated beta-galactosidase, increased expression of p53 and increased production of proinflammatory cytokines. Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease. Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from individuals with diabetes also showed senescence-like features. Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes (pages 996-967).
10.1038/nm.2014
p53-induced adipose tissue inflammation is critically involved in the development of insulin resistance in heart failure.
Shimizu Ippei,Yoshida Yohko,Katsuno Taro,Tateno Kaoru,Okada Sho,Moriya Junji,Yokoyama Masataka,Nojima Aika,Ito Takashi,Zechner Rudolf,Komuro Issei,Kobayashi Yoshio,Minamino Tohru
Cell metabolism
Several clinical studies have shown that insulin resistance is prevalent among patients with heart failure, but the underlying mechanisms have not been fully elucidated. Here, we report a mechanism of insulin resistance associated with heart failure that involves upregulation of p53 in adipose tissue. We found that pressure overload markedly upregulated p53 expression in adipose tissue along with an increase of adipose tissue inflammation. Chronic pressure overload accelerated lipolysis in adipose tissue. In the presence of pressure overload, inhibition of lipolysis by sympathetic denervation significantly downregulated adipose p53 expression and inflammation, thereby improving insulin resistance. Likewise, disruption of p53 activation in adipose tissue attenuated inflammation and improved insulin resistance but also ameliorated cardiac dysfunction induced by chronic pressure overload. These results indicate that chronic pressure overload upregulates adipose tissue p53 by promoting lipolysis via the sympathetic nervous system, leading to an inflammatory response of adipose tissue and insulin resistance.
10.1016/j.cmet.2011.12.006
Mechanisms of aging-related impairment of brown adipocyte development and function.
Graja Antonia,Schulz Tim J
Gerontology
Aging is one of the primary risk factors for the development of obesity, a pathology that develops due to an imbalance of increased energy consumption over reduced expenditure. Brown adipocytes are responsible for thermogenesis and could therefore counter obesity by increasing energy expenditure. It is by now well established that humans possess thermogenesis-competent brown adipocytes throughout life, and recent findings indicate that brown fat is actively involved in metabolic control and body weight regulation in adults. Aging is accompanied by a loss of classical brown adipocytes as well as the brown-like adipocytes found in white adipose tissue, suggesting that loss of their energy-expending capacity might contribute to an obesity-prone phenotype with increased age. We here discuss the hypothesis that the age-related loss of brown adipocyte regenerative capacity is a result of dysfunctional stem/progenitor cells. The possible molecular mechanisms that lead to an age-related decline in brown adipogenic stem/progenitor cell function include cell-autonomous and external effects. General loss of mitochondrial biogenesis and function has repeatedly been linked to age-related perturbation of metabolic processes. We also discuss the possibility that alterations in neuronal control by the sympathetic nervous system may contribute to impaired regeneration and thermogenesis in aged brown adipocytes. Finally, age-related changes of endocrine signals have been proposed to exacerbate the loss of brown adipose tissue. In conclusion, age-induced impairment of brown adipogenic stem/progenitor cell function could contribute to the loss of brown adipocyte regeneration, thereby promoting the development of obesity and other metabolic disorders with age.
10.1159/000366557
Interleukin-6 Knockout Inhibits Senescence of Bone Mesenchymal Stem Cells in High-Fat Diet-Induced Bone Loss.
Li Yujue,Lu Lingyun,Xie Ying,Chen Xiang,Tian Li,Liang Yan,Li Huifang,Zhang Jie,Liu Yi,Yu Xijie
Frontiers in endocrinology
Obesity, a chronic low-grade inflammatory state, not only promotes bone loss, but also accelerates cell senescence. However, little is known about the mechanisms that link obesity, bone loss, and cell senescence. Interleukin-6 (IL-6), a pivotal inflammatory mediator increased during obesity, is a candidate for promoting cell senescence and an important part of senescence-associated secretory phenotype (SASP). Here, wild type (WT) and (IL-6 KO) mice were fed with high-fat diet (HFD) for 12 weeks. The results showed IL-6 KO mice gain less weight on HFD than WT mice. HFD induced trabecular bone loss, enhanced expansion of bone marrow adipose tissue (BMAT), increased adipogenesis in bone marrow (BM), and reduced the bone formation in WT mice, but it failed to do so in IL-6 KO mice. Furthermore, IL-6 KO inhibited HFD-induced clone formation of bone marrow cells (BMCs), and expression of senescence markers (p53 and p21). IL-6 antibody inhibited the activation of STAT3 and the senescence of bone mesenchymal stem cells (BMSCs) from WT mice , while rescued IL-6 induced senescence of BMSCs from IL-6 KO mice through the STAT3/p53/p21 pathway. In summary, our data demonstrated that IL-6 KO may maintain the balance between osteogenesis and adipogenesis in BM, and restrain senescence of BMSCs in HFD-induced bone loss.
10.3389/fendo.2020.622950
Postprandial triglyceride-rich lipoproteins-induced premature senescence of adipose-derived mesenchymal stem cells via the SIRT1/p53/Ac-p53/p21 axis through oxidative mechanism.
Xiang Qun-Yan,Tian Feng,Du Xiao,Xu Jin,Zhu Li-Yuan,Guo Li-Ling,Wen Tie,Liu You-Shuo,Liu Ling
Aging
The accumulation of senescent adipose-derived mesenchymal stem cells (AMSCs) in subcutaneous white adipose tissue (WAT) is the main cause for the deterioration of WAT and the subsequent age-related disorders in obesity. The number of AMSCs staining positively for senescence-associated-β-galactosidase (SA-β-Gal) increased significantly after incubation with postprandial triglyceride-rich lipoproteins (TRL), accompanied by an impaired cell proliferation capacity and increased expression of inflammatory factors. Besides, the expression of anti-aging protein, silent mating-type information regulation 2 homolog 1 (SIRT1), was downregulated significantly, while those of acetylated p53 (Ac-p53), total p53, and p21 proteins were upregulated significantly during postprandial TRL-induced premature senescence of AMSCs. Furthermore, the production of intracellular reactive oxygen species (ROS) in the TRL group increased significantly, while pretreatment with the ROS scavenger N-acetyl-L-cysteine effectively attenuated the premature senescence of AMSCs by decreasing ROS production and upregulating SIRT1 level. Thus, postprandial TRL induced premature senescence of AMSCs through the SIRT1/p53/Ac-p53/p21 axis, partly through increased oxidative stress.
10.18632/aging.202298
Identification of with potential roles in metabolic disorders.
Peng Hui,Guo Qi,Su Tian,Xiao Ye,Li Chang-Jun,Huang Yan,Luo Xiang-Hang
Aging
Obesity is characterized by the expansion of adipose tissue which is partially modulated by adipogenesis. In the present study, we identified five differentially expressed genes by incorporating two adipogenesis-related datasets from the GEO database and their correlation with adipogenic markers. However, the role of scavenger receptor class A member 3 () in obesity-related disorders has been rarely reported. We found that expression in old adipose tissue-derived mesenchymal stem cells (Ad-MSCs) was lower than it in young Ad-MSCs. Obese mice caused by deletion of the leptin receptor gene () or by a high-fat diet both showed reduced expression in inguinal white adipose tissue. Moreover, hypermethylation of was observed in patients with type 2 diabetes and atherosclerosis. Data from the CTD database indicated that is a potential target for metabolic diseases. Mechanistically, was predicted as a transcriptional factor of in different databases which is consistent with our further bioinformatics analysis. Collectively, our study suggested that is potentially associated with age-related metabolic dysfunction, which provided new insights into the pathogenesis and treatment of obesity as well as other obesity-associated metabolic complications.
10.18632/aging.202228
Identity, proliferation capacity, genomic stability and novel senescence markers of mesenchymal stem cells isolated from low volume of human bone marrow.
Kundrotas Gabrielis,Gasperskaja Evelina,Slapsyte Grazina,Gudleviciene Zivile,Krasko Jan,Stumbryte Ausra,Liudkeviciene Regina
Oncotarget
Human bone marrow mesenchymal stem cells (hBM-MSCs) hold promise for treating incurable diseases and repairing of damaged tissues. However, hBM-MSCs face the disadvantages of painful invasive isolation and limited cell numbers. In this study we assessed characteristics of MSCs isolated from residual human bone marrow transplantation material and expanded to clinically relevant numbers at passages 3-4 and 6-7. Results indicated that early passage hBM-MSCs are genomically stable and retain identity and high proliferation capacity. Despite the chromosomal stability, the cells became senescent at late passages, paralleling the slower proliferation, altered morphology and immunophenotype. By qRT-PCR array profiling, we revealed 13 genes and 33 miRNAs significantly differentially expressed in late passage cells, among which 8 genes and 30 miRNAs emerged as potential novel biomarkers of hBM-MSC aging. Functional analysis of genes with altered expression showed strong association with biological processes causing cellular senescence. Altogether, this study revives hBM as convenient source for cellular therapy. Potential novel markers provide new details for better understanding the hBM-MSC senescence mechanisms, contributing to basic science, facilitating the development of cellular therapy quality control, and providing new clues for human disease processes since senescence phenotype of the hematological patient hBM-MSCs only very recently has been revealed.
10.18632/oncotarget.7456
Metabolism as an early predictor of DPSCs aging.
Macrin Dannie,Alghadeer Ammar,Zhao Yan Ting,Miklas Jason W,Hussein Abdiasis M,Detraux Damien,Robitaille Aaron M,Madan Anup,Moon Randall T,Wang Yuliang,Devi Arikketh,Mathieu Julie,Ruohola-Baker Hannele
Scientific reports
Tissue resident adult stem cells are known to participate in tissue regeneration and repair that follows cell turnover, or injury. It has been well established that aging impedes the regeneration capabilities at the cellular level, but it is not clear if the different onset of stem cell aging between individuals can be predicted or prevented at an earlier stage. Here we studied the dental pulp stem cells (DPSCs), a population of adult stem cells that is known to participate in the repair of an injured tooth, and its properties can be affected by aging. The dental pulp from third molars of a diverse patient group were surgically extracted, generating cells that had a high percentage of mesenchymal stem cell markers CD29, CD44, CD146 and Stro1 and had the ability to differentiate into osteo/odontogenic and adipogenic lineages. Through RNA seq and qPCR analysis we identified homeobox protein, Barx1, as a marker for DPSCs. Furthermore, using high throughput transcriptomic and proteomic analysis we identified markers for DPSC populations with accelerated replicative senescence. In particular, we show that the transforming growth factor-beta (TGF-β) pathway and the cytoskeletal proteins are upregulated in rapid aging DPSCs, indicating a loss of stem cell characteristics and spontaneous initiation of terminal differentiation. Importantly, using metabolic flux analysis, we identified a metabolic signature for the rapid aging DPSCs, prior to manifestation of senescence phenotypes. This metabolic signature therefore can be used to predict the onset of replicative senescence. Hence, the present study identifies Barx1 as a DPSCs marker and dissects the first predictive metabolic signature for DPSCs aging.
10.1038/s41598-018-37489-4
Transcriptome profiles acquired during cell expansion and licensing validate mesenchymal stromal cell lineage genes.
Wiese Danielle M,Braid Lorena R
Stem cell research & therapy
BACKGROUND:Mesenchymal stromal cells (MSCs) are rapidly advancing as commercial therapeutics. However, there are still no adequate tools to validate the identity of MSCs and support standardization of MSC-based products. Currently accepted metrics include cell surface marker profiling and tri-lineage differentiation assays, neither of which is definitive. Transcript profiling represents a cost- and time-effective approach amenable to MSC manufacturing processes. Two independent labs recently reported non-overlapping MSC-specific transcriptomic signatures of 489 and 16 genes. METHODS:Here, we interrogated our repository of transcriptome data to determine whether routine culture manipulations including cell expansion and immune activation affect expression of the reported MSC lineage genes. These data sets comprise 4 donor populations of human umbilical cord (UC) MSCs serially cultured from cryopreservation thaw through pre-senescence, and 3 donor populations each of naïve UC and bone marrow (BM) MSCs and licensed by 3 different cytokines. RESULTS:Overall, 437 of 456 proposed signature genes assessed in these data sets were reliably expressed, representing an enduring lineage profile in 96% agreement with the previous studies. Serial passaging resulted in the downregulation of 3 signature genes, and one was silenced. Cytokine stimulation downregulated expression of 16 signature genes, and 3 were uniformly silenced in one or the other MSC type. Fifteen additional genes were unreliably detected, independent of culture manipulation. CONCLUSION:These results validate and refine the proposed transcriptomic tools for reliable identification of MSCs after isolation through cell expansion and after inflammatory activation. We propose a 24-gene signature to support standardized and accessible MSC characterization.
10.1186/s13287-020-01873-7
Accumulating Transcriptome Drift Precedes Cell Aging in Human Umbilical Cord-Derived Mesenchymal Stromal Cells Serially Cultured to Replicative Senescence.
Wiese Danielle M,Ruttan Cindy C,Wood Catherine A,Ford Barry N,Braid Lorena R
Stem cells translational medicine
In preclinical studies, mesenchymal stromal cells (MSCs) exhibit robust potential for numerous applications. To capitalize on these benefits, cell manufacturing and delivery protocols have been scaled up to facilitate clinical trials without adequately addressing the impact of these processes on cell utility nor inevitable regulatory requirements for consistency. Growing evidence indicates that culture-aged MSCs, expanded to the limits of replicative exhaustion to generate human doses, are not equivalent to early passage cells, and their use may underpin reportedly underwhelming or inconsistent clinical outcomes. Here, we sought to define the maximum expansion boundaries for human umbilical cord-derived MSCs, cultured in chemically defined xeno- and serum-free media, that yield consistent cell batches comparable to early passage cells. Two male and two female donor populations, recovered from cryostorage at mean population doubling level (mPDL) 10, were serially cultivated until replicative exhaustion (senescence). At each passage, growth kinetics, cell morphology, and transcriptome profiles were analyzed. All MSC populations displayed comparable growth trajectories through passage 9 (P9; mPDL 45) and variably approached senescence after P10 (mPDL 49). Transcription profiles of 14,500 human genes, generated by microarray, revealed a nonlinear evolution of culture-adapted MSCs. Significant expression changes occurred only after P5 (mPDL 27) and accumulated rapidly after P9 (mPDL 45), preceding other cell aging metrics. We report that cryobanked umbilical cord-derived MSCs can be reliably expanded to clinical human doses by P4 (mPDL 23), before significant transcriptome drift, and thus represent a mesenchymal cell source suited for clinical translation of cellular therapies. Stem Cells Translational Medicine 2019;8:945&958.
10.1002/sctm.18-0246
FZD5 regulates cellular senescence in human mesenchymal stem/stromal cells.
Harada Seiko,Mabuchi Yo,Kohyama Jun,Shimojo Daisuke,Suzuki Sadafumi,Kawamura Yoshimi,Araki Daisuke,Suyama Takashi,Kajikawa Masunori,Akazawa Chihiro,Okano Hideyuki,Matsuzaki Yumi
Stem cells (Dayton, Ohio)
Human mesenchymal stem/stromal cells (hMSCs) have garnered enormous interest as a potential resource for cell-based therapies. However, the molecular mechanisms regulating senescence in hMSCs remain unclear. To elucidate these mechanisms, we performed gene expression profiling to compare clonal immature MSCs exhibiting multipotency with less potent MSCs. We found that the transcription factor Frizzled 5 (FZD5) is expressed specifically in immature hMSCs. The FZD5 cell surface antigen was also highly expressed in the primary MSC fraction (LNGFR THY-1 ) and cultured MSCs. Treatment of cells with the FZD5 ligand WNT5A promoted their proliferation. Upon FZD5 knockdown, hMSCs exhibited markedly attenuated proliferation and differentiation ability. The observed increase in the levels of senescence markers suggested that FZD5 knockdown promotes cellular senescence by regulating the noncanonical Wnt pathway. Conversely, FZD5 overexpression delayed cell cycle arrest during the continued culture of hMSCs. These results indicated that the intrinsic activation of FZD5 plays an essential role in negatively regulating senescence in hMSCs and suggested that controlling FZD5 signaling offers the potential to regulate hMSC quality and improve the efficacy of cell-replacement therapies using hMSCs.
10.1002/stem.3317
Du-Huo-Ji-Sheng-Tang and its active component Ligusticum chuanxiong promote osteogenic differentiation and decrease the aging process of human mesenchymal stem cells.
Wang Jir-You,Chen Wei-Ming,Wen Che-Sheng,Hung Shih-Chieh,Chen Pei-Wen,Chiu Jen-Hwey
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Postmenopausal osteoporosis is the most common bone disease worldwide. Information concerning the effects of herbal medicines on mesenchymal cell osteogenesis and senescence remains lacking. AIM OF THIS STUDY:This study was designed to investigate the effects of Du-Huo-Ji-Sheng-Tang (DHJST), a Chinese herbal medicine and its active component Ligusticum chuanxiong on osteogenic differentiation and the aging process of human mesenchymal cells (hMSCs). MATERIALS & METHODS:hMSCs were used as in vitro model and osteogenesis was induced by administration of either osteogenesis inducing medium (OIM) or dexamethasone-depleted OIM (DDOIM) for 1-week or 2 weeks and the results were evaluated by measuring the formation of mineralization nodules. The effects of the compound recipe DHJST and its active component L. chuanxiong on hMSCs osteogenesis-related gene expression was determined by real-time PCR that targeted bone morphogenetic protein-2 (BMP2), RUNX2, ALP, COL-1, osteopontin (OPN), and osteocalcin (OCN). Antibodies against BMP-related signaling pathway proteins, such as BMP-2, ERK, SMAD 1/5/8, and RUNX2, were also detected at the protein level by Western blotting. Finally, the cumulative growth curve and senescence of the hMSCs were evaluated in order to assess the aging process. RESULTS:L. chuanxiong increased osteogenic activity in hMSCs and up-regulated BMP-2 and RUNX2 gene expression via the activation of SMAD 1/5/8 and ERK signaling. Furthermore DHJST also showed a trend towards promoting the same effects in the same system. In the absence of dexamethasone, DHJST did activate SMAD 1/5/8 and ERK signaling and hence increased RUNX2 protein expression in hMSCs. In addition, both DHJST and L. chuanxiong delayed the hMSCs aging process by decreasing cell senescence. CONCLUSIONS:We concluded that DHJST and its active component L. chuanxiong are able to promote osteogenic activity and decrease hMSCs senescence as cells age.
10.1016/j.jep.2016.12.011
Transcriptome and lipidome profile of human mesenchymal stem cells with reduced senescence and increased trilineage differentiation ability upon drug treatment.
Chen Yue,An Xinglan,Wang Zengmiao,Guan Shuanghong,An Hongyu,Huang Qingyuan,Zhang Haobo,Liang Lin,Huang Bo,Wang Huiyu,Lu Min,Nie Huan,Wang Jun,Dai Xiangpeng,Lu Xin
Aging
Human Mesenchymal stem cells (hMSCs) are multi-potential cells which are widely used in cell therapy. However, the frequently emerged senescence and decrease of differentiation capabilities limited the broad applications of MSC. Several strategies such as small molecules treatment have been widely studied and used to improve the stem characteristics bypassing the senescence but the exact mechanisms for them to reduce senescence have not been fully studied. In this study, hMSCs were treated by rapamycin, oltipraz, metformin, and vitamin C for the indicated time and these cells were subjected to senescence evaluation and trilineage differentiation. Furthermore, transcriptomics and lipidomics datasets of hMSCs after drug treatment were analyzed to interpret biological pathways responsible for their anti-senescence effects. Although four drugs exhibited significant activities in promoting MSC osteogenic differentiation, metformin is the optimal drug to promote trilineage differentiation. GO terms illustrated that the anti-aging effects of drugs were mainly associated with cellular senescence, mitotic and meiosis process. Biosynthesis of phosphatidylcholines (PC) and phosphatidylethanolamine (PE) were inhibited whereas production of phosphatidylinositols (PIs) and saturated fatty acids (SFA)/ mono-unsaturated fatty acids (MUFA) conversion was activated. Medium free fatty acids (FFA) was increased in hMSCs with different anti-aging phenotypes. Therefore, we established a comprehensive method in assessing drug intervention based on the results of transcriptomics and lipidomics. The method can be used to study different biological phenotypes upon drug intervention in MSC which will extend the clinical application of hMSCs.
10.18632/aging.202759
Ganoderic Acid D Protects Human Amniotic Mesenchymal Stem Cells against Oxidative Stress-Induced Senescence through the PERK/NRF2 Signaling Pathway.
Xu Yan,Yuan Huan,Luo Yi,Zhao Yu-Jie,Xiao Jian-Hui
Oxidative medicine and cellular longevity
Aging is an important risk factor in the occurrence of many chronic diseases. Senescence and exhaustion of adult stem cells are considered as a hallmark of aging in organisms. In this study, a senescent human amniotic mesenchymal stem cell (hAMSC) model subjected to oxidative stress was established using hydrogen peroxide. We investigated the effects of ganoderic acid D (GA-D), a natural triterpenoid compound produced from , on hAMSC senescence. GA-D significantly inhibited -galactosidase (a senescence-associated marker) formation, in a dose-dependent manner, with doses ranging from 0.1 M to 10 M, without inducing cytotoxic side-effects. Furthermore, GA-D markedly inhibited the generation of reactive oxygen species (ROS) and the expression of p21 and p16 proteins, relieved the cell cycle arrest, and enhanced telomerase activity in senescent hAMSCs. Furthermore, GA-D upregulated the expression of phosphorylated protein kinase R- (PKR-) like endoplasmic reticulum kinase (PERK), peroxidase III (PRDX3), and nuclear factor-erythroid 2-related factor (NRF2) and promoted intranuclear transfer of NRF2 in senescent cells. The PERK inhibitor GSK2656157 and/or the NRF2 inhibitor ML385 suppressed the PERK/NRF2 signaling, which was activated by GA-D. They induced a rebound for the generation of ROS and -galactosidase-positive cells and attenuated the differentiation capacity. These findings suggest that GA-D retards hAMSC senescence through activation of the PERK/NRF2 signaling pathway and may be a promising candidate for the discovery of antiaging agents.
10.1155/2020/8291413
Vitamin C Treatment Rescues Prelamin A-Induced Premature Senescence of Subchondral Bone Mesenchymal Stem Cells.
Qu Yan-Nv,Zhang Li,Wang Ting,Zhang He-Yang,Yang Ze-Ji,Yuan Fang-Fang,Wang Yan,Li Si-Wei,Jiang Xiao-Xia,Xie Xiao-Hua
Stem cells international
Aging is a predominant risk factor for many chronic conditions. Stem cell dysfunction plays a pivotal role in the aging process. Prelamin A, an abnormal processed form of the nuclear lamina protein lamin A, has been reported to trigger premature senescence. However, the mechanism driving stem cell dysfunction is still unclear. In this study, we found that while passaging subchondral bone mesenchymal stem cells (SCB-MSCs) , prelamin A accumulation occurred concomitantly with an increase in senescence-associated -galactosidase (SA--Gal) expression. Unlike their counterparts, SCB-MSCs with prelamin A overexpression (MSC/PLA) demonstrated decreased proliferation, osteogenesis, and adipogenesis but increased production of inflammatory factors. In a hind-limb ischemia model, MSC/PLA also exhibited compromised therapy effect. Further investigation showed that exogenous prelamin A triggered abnormal nuclear morphology, DNA and shelterin complex damage, cell cycle retardation, and eventually cell senescence. Changes in gene expression profile were also verified by microarray assay. Interestingly, we found that ascorbic acid or vitamin C (VC) treatment could inhibit prelamin A expression in MSC/PLA and partially reverse the premature aging in MSC/PLA, with reduced secretion of inflammatory factors and cell cycle arrest and resistance to apoptosis. Importantly, after VC treatment, MSC/PLA showed enhanced therapy effect in the hind-limb ischemia model. In conclusion, prelamin A can accelerate SCB-MSC premature senescence by inducing DNA damage. VC can be a potential therapeutic reagent for prelamin A-induced aging defects in MSCs.
10.1155/2020/3150716
Coenzyme Q10 inhibits the aging of mesenchymal stem cells induced by D-galactose through Akt/mTOR signaling.
Zhang Dayong,Yan Bingxi,Yu Shanshan,Zhang Chong,Wang Baoming,Wang Yayan,Wang Junbo,Yuan Zhanggen,Zhang Lihuang,Pan Jianping
Oxidative medicine and cellular longevity
Increasing evidences indicate that reactive oxygen species are the main factor promoting stem cell aging. Recent studies have demonstrated that coenzyme Q10 (CoQ10) plays a positive role in organ and cellular aging. However, the potential for CoQ10 to protect stem cell aging has not been fully evaluated, and the mechanisms of cell senescence inhibited by CoQ10 are still poorly understood. Our previous study had indicated that D-galactose (D-gal) can remarkably induce mesenchymal stem cell (MSC) aging through promoting intracellular ROS generation. In this study, we showed that CoQ10 could significantly inhibit MSC aging induced by D-gal. Moreover, in the CoQ10 group, the expression of p-Akt and p-mTOR was clearly reduced compared with that in the D-gal group. However, after Akt activating by CA-Akt plasmid, the senescence-cell number in the CoQ10 group was significantly higher than that in the control group. These results indicated that CoQ10 could inhibit D-gal-induced MSC aging through the Akt/mTOR signaling.
10.1155/2015/867293
1,25-Dihydroxyvitamin D insufficiency accelerates age-related bone loss by increasing oxidative stress and cell senescence.
Qiao Wanxin,Yu Shuxiang,Sun Haijian,Chen Lulu,Wang Rong,Wu Xuan,Goltzman David,Miao Dengshun
American journal of translational research
We investigated the role of insufficiency of the active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)D] in age-related bone loss. We employed mice with heterozygous deletion of , the gene encoding the enzyme that synthesizes 1,25(OH)D, as a model for 1,25(OH)D insufficiency and compared the phenotype of lumber vertebrae from 3-, 9- and 18-month-old mice and their wild-type littermates. We found that in wild-type mice, bone mineral density, bone volume, and protein expression levels decreased progressively with age, accompanied by declining osteoblastic bone formation and increasing osteoclastic bone resorption, however these age-related skeletal alterations were more severe in mice which had significantly lower serum 1,25(OH)D levels. We then assessed the effect of 1,25(OH)D haploinsufficiency on oxidative stress and DNA damage, cell senescence and senescence-associated secretory phenotype (SASP) in 9-month-old wild-type and mice. Our results demonstrated that, in mice compared with their wild-type littermates, the parameters of oxidative stress and DNA damage were significantly increased, whereas the expression levels of antioxidant enzymes were significantly down-regulated; the percentage of senescent osteocytes and bone marrow mesenchymal stem cells, and the expression levels of SASP molecules and p16, p19 and p53 proteins were all significantly increased in bone tissues. Taken together, the results of this study indicate that 1,25(OH)D insufficiency accelerates age-related bone loss by increasing oxidative stress and DNA damage, inducing bone cell senescence and SASP, and subsequently inhibiting osteoblastic bone formation while stimulating osteoclastic bone resorption.
Ascorbic acid inhibits senescence in mesenchymal stem cells through ROS and AKT/mTOR signaling.
Yang Mengkai,Teng Songsong,Ma Chunhui,Yu Yinxian,Wang Peilin,Yi Chengqing
Cytotechnology
Mesenchymal stem cell (MSC) aging seriously affects its function in stem cell transplantation for treatment. Extensive studies have focused on how to inhibit senescence in MSCs. However, the mechanism of senescence in MSC was not clear. In this study, we used D-galactose to induce MSC aging. Then we found that the number of aging cells was increased compared with untreated MSCs. We discovered that ascorbic acid could inhibit the production of reactive oxygen species (ROS) and activation of AKT/mTOR signaling in MSCs caused by D-galactose. Especially, when treated together with a ROS scavenger or AKT inhibitor, the senescent cells were obviously decreased in D-galactose-induced MSCs. Taken together, we identify that ascorbic acid owns the potential to inhibit the senescence of MSCs through ROS and Akt/mTOR signaling. Together, our data supports that ascorbic acid can be used to prevent MSCs from senescence, which can enhance the efficiency of stem cell transplantation in the clinic.
10.1007/s10616-018-0220-x
Vitamin C treatment promotes mesenchymal stem cell sheet formation and tissue regeneration by elevating telomerase activity.
Wei Fulan,Qu Cunye,Song Tieli,Ding Gang,Fan Zhipeng,Liu Dayong,Liu Yi,Zhang Chunmei,Shi Songtao,Wang Songlin
Journal of cellular physiology
Cell sheet engineering has been developed as an alternative approach to improve mesenchymal stem cell-mediated tissue regeneration. In this study, we found that vitamin C (Vc) was capable of inducing telomerase activity in periodontal ligament stem cells (PDLSCs), leading to the up-regulated expression of extracellular matrix type I collagen, fibronectin, and integrin β1, stem cell markers Oct4, Sox2, and Nanog as well as osteogenic markers RUNX2, ALP, OCN. Under Vc treatment, PDLSCs can form cell sheet structures because of increased cell matrix production. Interestingly, PDLSC sheets demonstrated a significant improvement in tissue regeneration compared with untreated control dissociated PDLSCs and offered an effective treatment for periodontal defects in a swine model. In addition, bone marrow mesenchymal stem cell sheets and umbilical cord mesenchymal stem cell sheets were also well constructed using this method. The development of Vc-mediated mesenchymal stem cell sheets may provide an easy and practical approach for cell-based tissue regeneration.
10.1002/jcp.24012