Lin He, Chen Zhu, Xiang-Feng Zhou, Shu-E Zeng, Le Zhang, Kuan Li
Proliferation and differentiation of intestinal stem cell (ISC) to replace damaged gut mucosal epithelial cells in inflammatory states is a critical step in ameliorating gut inflammation. However, when this disordered proliferation continues, it induces the ISC to enter a cancerous state. The gut microbiota on the free surface of the gut mucosal barrier is able to interact with ISC on a sustained basis. Microbiota metabolites are able to regulate the proliferation of gut stem and progenitor cells through transcription factors, while in steady state, differentiated colonocytes are able to break down such metabolites, thereby protecting stem cells at the gut crypt. In the future, the gut flora and its metabolites mediating the regulation of ISC differentiation will be a potential treatment for enteropathies.
{"title":"Gut microbiota modulating intestinal stem cell differentiation.","authors":"Lin He, Chen Zhu, Xiang-Feng Zhou, Shu-E Zeng, Le Zhang, Kuan Li","doi":"10.4252/wjsc.v16.i6.619","DOIUrl":"10.4252/wjsc.v16.i6.619","url":null,"abstract":"<p><p>Proliferation and differentiation of intestinal stem cell (ISC) to replace damaged gut mucosal epithelial cells in inflammatory states is a critical step in ameliorating gut inflammation. However, when this disordered proliferation continues, it induces the ISC to enter a cancerous state. The gut microbiota on the free surface of the gut mucosal barrier is able to interact with ISC on a sustained basis. Microbiota metabolites are able to regulate the proliferation of gut stem and progenitor cells through transcription factors, while in steady state, differentiated colonocytes are able to break down such metabolites, thereby protecting stem cells at the gut crypt. In the future, the gut flora and its metabolites mediating the regulation of ISC differentiation will be a potential treatment for enteropathies.</p>","PeriodicalId":23775,"journal":{"name":"World journal of stem cells","volume":"16 6","pages":"619-622"},"PeriodicalIF":3.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Serdar Kabatas, Erdinç Civelek, Osman Boyalı, Gülseli Berivan Sezen, Omer Ozdemir, Yeliz Bahar-Ozdemir, Necati Kaplan, Eyüp Can Savrunlu, Erdal Karaöz
Background: Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. Stem cell transplantation has evolved as a novel treatment modality in the management of TBI, as it has the potential to arrest the degeneration and promote regeneration of new cells in the brain. Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) have recently shown beneficial effects in the functional recovery of neurological deficits.
Aim: To evaluate the safety and efficiency of MSC therapy in TBI.
Methods: We present 6 patients, 4 male and 2 female aged between 21 and 27 years who suffered a TBI. These 6 patients underwent 6 doses of intrathecal, intramuscular (i.m.) and intravenous transplantation of WJ-MSCs at a target dose of 1 × 106/kg for each application route. Spasticity was assessed using the Modified Ashworth scale (MAS), motor function according to the Medical Research Council Muscle Strength Scale, quality of life was assessed by the Functional Independence Measure (FIM) scale and Karnofsky Performance Status scale.
Results: Our patients showed only early, transient complications, such as subfebrile fever, mild headache, and muscle pain due to i.m. injection, which resolved within 24 h. During the one year follow-up, no other safety issues or adverse events were reported. These 6 patients showed improvements in their cognitive abilities, muscle spasticity, muscle strength, performance scores and fine motor skills when compared before and after the intervention. MAS values, which we used to assess spasticity, were observed to statistically significantly decrease for both left and right sides (P < 0.001). The FIM scale includes both motor scores (P < 0.05) and cognitive scores (P < 0.001) and showed a significant increase in pretest posttest analyses. The difference observed in the participants' Karnofsky Performance Scale values pre and post the intervention was statistically significant (P < 0.001).
Conclusion: This study showed that cell transplantation has a safe, effective and promising future in the management of TBI.
{"title":"Safety and efficiency of Wharton's Jelly-derived mesenchymal stem cell administration in patients with traumatic brain injury: First results of a phase I study.","authors":"Serdar Kabatas, Erdinç Civelek, Osman Boyalı, Gülseli Berivan Sezen, Omer Ozdemir, Yeliz Bahar-Ozdemir, Necati Kaplan, Eyüp Can Savrunlu, Erdal Karaöz","doi":"10.4252/wjsc.v16.i6.641","DOIUrl":"10.4252/wjsc.v16.i6.641","url":null,"abstract":"<p><strong>Background: </strong>Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. Stem cell transplantation has evolved as a novel treatment modality in the management of TBI, as it has the potential to arrest the degeneration and promote regeneration of new cells in the brain. Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) have recently shown beneficial effects in the functional recovery of neurological deficits.</p><p><strong>Aim: </strong>To evaluate the safety and efficiency of MSC therapy in TBI.</p><p><strong>Methods: </strong>We present 6 patients, 4 male and 2 female aged between 21 and 27 years who suffered a TBI. These 6 patients underwent 6 doses of intrathecal, intramuscular (i.m.) and intravenous transplantation of WJ-MSCs at a target dose of 1 × 10<sup>6</sup>/kg for each application route. Spasticity was assessed using the Modified Ashworth scale (MAS), motor function according to the Medical Research Council Muscle Strength Scale, quality of life was assessed by the Functional Independence Measure (FIM) scale and Karnofsky Performance Status scale.</p><p><strong>Results: </strong>Our patients showed only early, transient complications, such as subfebrile fever, mild headache, and muscle pain due to i.m. injection, which resolved within 24 h. During the one year follow-up, no other safety issues or adverse events were reported. These 6 patients showed improvements in their cognitive abilities, muscle spasticity, muscle strength, performance scores and fine motor skills when compared before and after the intervention. MAS values, which we used to assess spasticity, were observed to statistically significantly decrease for both left and right sides (<i>P</i> < 0.001). The FIM scale includes both motor scores (<i>P</i> < 0.05) and cognitive scores (<i>P</i> < 0.001) and showed a significant increase in pretest posttest analyses. The difference observed in the participants' Karnofsky Performance Scale values pre and post the intervention was statistically significant (<i>P</i> < 0.001).</p><p><strong>Conclusion: </strong>This study showed that cell transplantation has a safe, effective and promising future in the management of TBI.</p>","PeriodicalId":23775,"journal":{"name":"World journal of stem cells","volume":"16 6","pages":"641-655"},"PeriodicalIF":3.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Pelvic organ prolapse (POP) involves pelvic organ herniation into the vagina due to pelvic floor tissue laxity, and vaginal structure is an essential factor. In POP, the vaginal walls exhibit abnormal collagen distribution and decreased fibroblast levels and functions. The intricate etiology of POP and the prohibition of transvaginal meshes in pelvic reconstruction surgery present challenges in targeted therapy development. Human umbilical cord mesenchymal stromal cells (hucMSCs) present limitations, but their exosomes (hucMSC-Exo) are promising therapeutic tools for promoting fibroblast proliferation and extracellular matrix remodeling.
Aim: To investigate the effects of hucMSC-Exo on the functions of primary vaginal fibroblasts and to elucidate the underlying mechanism involved.
Methods: Human vaginal wall collagen content was assessed by Masson's trichrome and Sirius blue staining. Gene expression differences in fibroblasts from patients with and without POP were assessed via RNA sequencing (RNA-seq). The effects of hucMSC-Exo on fibroblasts were determined via functional experiments in vitro. RNA-seq data from fibroblasts exposed to hucMSC-Exo and microRNA (miRNA) sequencing data from hucMSC-Exo were jointly analyzed to identify effective molecules.
Results: In POP, the vaginal wall exhibited abnormal collagen distribution and reduced fibroblast 1 quality and quantity. Treatment with 4 or 6 μg/mL hucMSC-Exo suppressed inflammation in POP group fibroblasts, stimulated primary fibroblast growth, and elevated collagen I (Col1) production in vitro. High-throughput RNA-seq of fibroblasts treated with hucMSC-Exo and miRNA sequencing of hucMSC-Exo revealed that abundant exosomal miRNAs downregulated matrix metalloproteinase 11 (MMP11) expression.
Conclusion: HucMSC-Exo normalized the growth and function of primary fibroblasts from patients with POP by promoting cell growth and Col1 expression in vitro. Abundant miRNAs in hucMSC-Exo targeted and downregulated MMP11 expression. HucMSC-Exo-based therapy may be ideal for safely and effectively treating POP.
背景:盆腔脏器脱垂(POP)是指由于盆底组织松弛导致盆腔脏器疝入阴道,而阴道结构是一个重要因素。POP 患者的阴道壁胶原蛋白分布异常,成纤维细胞水平和功能下降。POP 的病因错综复杂,而且盆腔重建手术中禁止使用经阴道网,这给靶向疗法的开发带来了挑战。人脐带间充质基质细胞(hucMSCs)存在局限性,但其外泌体(hucMSC-Exo)是促进成纤维细胞增殖和细胞外基质重塑的有前途的治疗工具。通过 RNA 测序(RNA-seq)评估了 POP 患者和非 POP 患者成纤维细胞的基因表达差异。通过体外功能实验确定了 hucMSC-Exo 对成纤维细胞的影响。对暴露于 hucMSC-Exo 的成纤维细胞的 RNA-seq 数据和 hucMSC-Exo 的 microRNA (miRNA) 测序数据进行了联合分析,以确定有效分子:结果:POP 患者的阴道壁胶原分布异常,成纤维细胞 1 的质量和数量下降。用 4 或 6 μg/mL hucMSC-Exo 治疗可抑制 POP 组成纤维细胞的炎症反应,刺激原发性成纤维细胞生长,并提高体外胶原蛋白 I(Col1)的生成。用hucMSC-Exo处理成纤维细胞的高通量RNA-seq和hucMSC-Exo的miRNA测序显示,丰富的外泌体miRNA下调了基质金属蛋白酶11(MMP11)的表达:结论:HucMSC-Exo通过促进细胞生长和体外Col1的表达,使POP患者原代成纤维细胞的生长和功能正常化。hucMSC-Exo中丰富的miRNAs靶向并下调了MMP11的表达。基于 HucMSC-Exo 的疗法可能是安全有效治疗 POP 的理想方法。
{"title":"Exosomes from umbilical cord mesenchymal stromal cells promote the collagen production of fibroblasts from pelvic organ prolapse.","authors":"Lei-Mei Xu, Xin-Xin Yu, Ning Zhang, Yi-Song Chen","doi":"10.4252/wjsc.v16.i6.708","DOIUrl":"10.4252/wjsc.v16.i6.708","url":null,"abstract":"<p><strong>Background: </strong>Pelvic organ prolapse (POP) involves pelvic organ herniation into the vagina due to pelvic floor tissue laxity, and vaginal structure is an essential factor. In POP, the vaginal walls exhibit abnormal collagen distribution and decreased fibroblast levels and functions. The intricate etiology of POP and the prohibition of transvaginal meshes in pelvic reconstruction surgery present challenges in targeted therapy development. Human umbilical cord mesenchymal stromal cells (hucMSCs) present limitations, but their exosomes (hucMSC-Exo) are promising therapeutic tools for promoting fibroblast proliferation and extracellular matrix remodeling.</p><p><strong>Aim: </strong>To investigate the effects of hucMSC-Exo on the functions of primary vaginal fibroblasts and to elucidate the underlying mechanism involved.</p><p><strong>Methods: </strong>Human vaginal wall collagen content was assessed by Masson's trichrome and Sirius blue staining. Gene expression differences in fibroblasts from patients with and without POP were assessed <i>via</i> RNA sequencing (RNA-seq). The effects of hucMSC-Exo on fibroblasts were determined <i>via</i> functional experiments <i>in vitro</i>. RNA-seq data from fibroblasts exposed to hucMSC-Exo and microRNA (miRNA) sequencing data from hucMSC-Exo were jointly analyzed to identify effective molecules.</p><p><strong>Results: </strong>In POP, the vaginal wall exhibited abnormal collagen distribution and reduced fibroblast 1 quality and quantity. Treatment with 4 or 6 μg/mL hucMSC-Exo suppressed inflammation in POP group fibroblasts, stimulated primary fibroblast growth, and elevated collagen I (Col1) production <i>in vitro</i>. High-throughput RNA-seq of fibroblasts treated with hucMSC-Exo and miRNA sequencing of hucMSC-Exo revealed that abundant exosomal miRNAs downregulated matrix metalloproteinase 11 (MMP11) expression.</p><p><strong>Conclusion: </strong>HucMSC-Exo normalized the growth and function of primary fibroblasts from patients with POP by promoting cell growth and Col1 expression <i>in vitro</i>. Abundant miRNAs in hucMSC-Exo targeted and downregulated MMP11 expression. HucMSC-Exo-based therapy may be ideal for safely and effectively treating POP.</p>","PeriodicalId":23775,"journal":{"name":"World journal of stem cells","volume":"16 6","pages":"708-727"},"PeriodicalIF":3.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mesenchymal stem/stromal cells are potential optimal cell sources for stem cell therapies, and pretreatment has proven to enhance cell vitality and function. In a recent publication, Li et al explored a new combination of pretreatment conditions. Here, we present an editorial to comment on their work and provide our view on mesenchymal stem/stromal cell precondition.
{"title":"Searching for the optimal precondition procedure for mesenchymal stem/stromal cell treatment: Facts and perspectives.","authors":"Yu-Dong Zhao, Yong-Can Huang, Wei-Shi Li","doi":"10.4252/wjsc.v16.i6.615","DOIUrl":"10.4252/wjsc.v16.i6.615","url":null,"abstract":"<p><p>Mesenchymal stem/stromal cells are potential optimal cell sources for stem cell therapies, and pretreatment has proven to enhance cell vitality and function. In a recent publication, Li <i>et al</i> explored a new combination of pretreatment conditions. Here, we present an editorial to comment on their work and provide our view on mesenchymal stem/stromal cell precondition.</p>","PeriodicalId":23775,"journal":{"name":"World journal of stem cells","volume":"16 6","pages":"615-618"},"PeriodicalIF":3.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease that affects premature infants. Although mounting evidence supports the therapeutic effect of exosomes on NEC, the underlying mechanisms remain unclear.
Aim: To investigate the mechanisms underlying the regulation of inflammatory response and intestinal barrier function by umbilical cord mesenchymal stem cell (UCMSCs) exosomes, as well as their potential in alleviating NEC in neonatal mice.
Methods: NEC was induced in 5-d-old C57BL/6 pups through hypoxia and gavage feeding of formula containing lipopolysaccharide (LPS), after which the mice received human UCMSC exosomes (hUCMSC-exos). The control mice were allowed to breastfeed with their dams. Ileal tissues were collected from the mice and analyzed by histopathology and immunoblotting. Colon tissues were collected from NEC neonates and analyzed by immunofluorescence. Molecular biology and cell culture approaches were employed to study the related mechanisms in intestinal epithelial cells.
Results: We found that autophagy is overactivated in intestinal epithelial cells during NEC, resulting in reduced expression of tight junction proteins and an increased inflammatory response. The ability of hUCMSC-exos to ameliorate NEC in a mouse model was dependent on decreased intestinal autophagy. We also showed that hUCMSC-exos alleviate the inflammatory response and increase migration ability in intestinal epithelial cells induced by LPS.
Conclusion: These results contribute to a better understanding of the protective mechanisms of hUCMSC-exos against NEC and provide a new theoretical and experimental foundation for NEC treatment. These findings also enhance our understanding of the role of the autophagy mechanism in NEC, offering potential avenues for identifying new therapeutic targets.
背景:坏死性小肠结肠炎(NEC坏死性小肠结肠炎(NEC)是一种影响早产儿的严重胃肠道疾病。目的:研究脐带间充质干细胞(UCMSCs)外泌体调节炎症反应和肠屏障功能的机制,以及外泌体缓解新生小鼠坏死性小肠结肠炎的潜力:方法:通过缺氧和灌胃含有脂多糖(LPS)的配方奶诱导5天大的C57BL/6幼鼠发生NEC,然后让小鼠接受人UCMSC外泌体(hUCMSC-exos)。对照组小鼠与母鼠一起进行母乳喂养。收集小鼠的回肠组织并进行组织病理学和免疫印迹分析。收集 NEC 新生儿的结肠组织并进行免疫荧光分析。采用分子生物学和细胞培养方法研究肠上皮细胞的相关机制:结果:我们发现自噬在 NEC 期间在肠上皮细胞中被过度激活,导致紧密连接蛋白表达减少和炎症反应增加。hUCMSC-exos 在小鼠模型中改善 NEC 的能力取决于肠道自噬的减少。我们还发现,hUCMSC-exos 可减轻 LPS 诱导的肠上皮细胞炎症反应并提高其迁移能力:这些结果有助于更好地理解 hUCMSC-exos 对 NEC 的保护机制,并为 NEC 治疗提供了新的理论和实验基础。这些发现还加深了我们对自噬机制在 NEC 中作用的理解,为确定新的治疗靶点提供了潜在途径。
{"title":"Umbilical cord mesenchymal stem cell exosomes alleviate necrotizing enterocolitis in neonatal mice by regulating intestinal epithelial cells autophagy.","authors":"Lin Zhu, Lu He, Wu Duan, Bo Yang, Ning Li","doi":"10.4252/wjsc.v16.i6.728","DOIUrl":"10.4252/wjsc.v16.i6.728","url":null,"abstract":"<p><strong>Background: </strong>Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease that affects premature infants. Although mounting evidence supports the therapeutic effect of exosomes on NEC, the underlying mechanisms remain unclear.</p><p><strong>Aim: </strong>To investigate the mechanisms underlying the regulation of inflammatory response and intestinal barrier function by umbilical cord mesenchymal stem cell (UCMSCs) exosomes, as well as their potential in alleviating NEC in neonatal mice.</p><p><strong>Methods: </strong>NEC was induced in 5-d-old C57BL/6 pups through hypoxia and gavage feeding of formula containing lipopolysaccharide (LPS), after which the mice received human UCMSC exosomes (hUCMSC-exos). The control mice were allowed to breastfeed with their dams. Ileal tissues were collected from the mice and analyzed by histopathology and immunoblotting. Colon tissues were collected from NEC neonates and analyzed by immunofluorescence. Molecular biology and cell culture approaches were employed to study the related mechanisms in intestinal epithelial cells.</p><p><strong>Results: </strong>We found that autophagy is overactivated in intestinal epithelial cells during NEC, resulting in reduced expression of tight junction proteins and an increased inflammatory response. The ability of hUCMSC-exos to ameliorate NEC in a mouse model was dependent on decreased intestinal autophagy. We also showed that hUCMSC-exos alleviate the inflammatory response and increase migration ability in intestinal epithelial cells induced by LPS.</p><p><strong>Conclusion: </strong>These results contribute to a better understanding of the protective mechanisms of hUCMSC-exos against NEC and provide a new theoretical and experimental foundation for NEC treatment. These findings also enhance our understanding of the role of the autophagy mechanism in NEC, offering potential avenues for identifying new therapeutic targets.</p>","PeriodicalId":23775,"journal":{"name":"World journal of stem cells","volume":"16 6","pages":"728-738"},"PeriodicalIF":3.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ying Gao, Mei-Fang Liu, Yang Li, Xi Liu, Yu-Jie Cao, Qian-Fa Long, Jun Yu, Jian-Ying Li
Background: Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation, causing structural damage and lung failure. Stem cell therapy and mesenchymal stem cells-extracellular vesicles (MSC-EVs) offer new hope for PF treatment.
Aim: To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis, oxidative stress, and immune inflammation in A549 cells and bleomycin (BLM)-induced mouse model.
Methods: The effect of MSC-EVs on A549 cells was assessed by fibrosis markers [collagen I and α-smooth muscle actin (α-SMA), oxidative stress regulators [nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and inflammatory regulators [nuclear factor-kappaB (NF-κB) p65, interleukin (IL)-1β, and IL-2]. Similarly, they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection. MSC-EVs ion PF mice were detected by pathological staining and western blot. Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice.
Results: Transforming growth factor (TGF)-β1 enhanced fibrosis in A549 cells, significantly increasing collagen I and α-SMA levels. Notably, treatment with MSC-EVs demonstrated a remarkable alleviation of these effects. Similarly, the expression of oxidative stress regulators, such as Nrf2 and HO-1, along with inflammatory regulators, including NF-κB p65 and IL-1β, were mitigated by MSC-EV treatment. Furthermore, in a parallel manner, MSC-EVs exhibited a downregulatory impact on collagen deposition, oxidative stress injuries, and inflammatory-related cytokines in the lungs of mice with PF. Additionally, the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response. The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes, oxidative stress, and inflammatory responses associated with PF.
Conclusion: MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition, oxidative stress, and immune-inflammatory responses.
{"title":"Mesenchymal stem cells-extracellular vesicles alleviate pulmonary fibrosis by regulating immunomodulators.","authors":"Ying Gao, Mei-Fang Liu, Yang Li, Xi Liu, Yu-Jie Cao, Qian-Fa Long, Jun Yu, Jian-Ying Li","doi":"10.4252/wjsc.v16.i6.670","DOIUrl":"10.4252/wjsc.v16.i6.670","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation, causing structural damage and lung failure. Stem cell therapy and mesenchymal stem cells-extracellular vesicles (MSC-EVs) offer new hope for PF treatment.</p><p><strong>Aim: </strong>To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis, oxidative stress, and immune inflammation in A549 cells and bleomycin (BLM)-induced mouse model.</p><p><strong>Methods: </strong>The effect of MSC-EVs on A549 cells was assessed by fibrosis markers [collagen I and α-smooth muscle actin (α-SMA), oxidative stress regulators [nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and inflammatory regulators [nuclear factor-kappaB (NF-κB) p65, interleukin (IL)-1β, and IL-2]. Similarly, they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection. MSC-EVs ion PF mice were detected by pathological staining and western blot. Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice.</p><p><strong>Results: </strong>Transforming growth factor (TGF)-β1 enhanced fibrosis in A549 cells, significantly increasing collagen I and α-SMA levels. Notably, treatment with MSC-EVs demonstrated a remarkable alleviation of these effects. Similarly, the expression of oxidative stress regulators, such as Nrf2 and HO-1, along with inflammatory regulators, including NF-κB p65 and IL-1β, were mitigated by MSC-EV treatment. Furthermore, in a parallel manner, MSC-EVs exhibited a downregulatory impact on collagen deposition, oxidative stress injuries, and inflammatory-related cytokines in the lungs of mice with PF. Additionally, the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response. The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes, oxidative stress, and inflammatory responses associated with PF.</p><p><strong>Conclusion: </strong>MSC-EVs could ameliorate fibrosis <i>in vitro</i> and <i>in vivo</i> by downregulating collagen deposition, oxidative stress, and immune-inflammatory responses.</p>","PeriodicalId":23775,"journal":{"name":"World journal of stem cells","volume":"16 6","pages":"670-689"},"PeriodicalIF":3.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kun-Chen Lin, Wen-Feng Fang, Jui-Ning Yeh, John Y Chiang, Hsin-Ju Chiang, Pei-Lin Shao, Pei-Hsun Sung, Hon-Kan Yip
<p><strong>Background: </strong>The treatment of acute respiratory distress syndrome (ARDS) complicated by sepsis syndrome (SS) remains challenging.</p><p><strong>Aim: </strong>To investigate whether combined adipose-derived mesenchymal-stem-cells (ADMSCs)-derived exosome (EX<sup>AD</sup>) and exogenous mitochondria (mito<sup>Ex</sup>) protect the lung from ARDS complicated by SS.</p><p><strong>Methods: </strong><i>In vitro</i> study, including L2 cells treated with lipopolysaccharide (LPS) and <i>in vivo</i> study including male-adult-SD rats categorized into groups 1 (sham-operated-control), 2 (ARDS-SS), 3 (ARDS-SS + EX<sup>AD</sup>), 4 (ARDS-SS + mito<sup>Ex</sup>), and 5 (ARDS-SS + EX<sup>AD</sup> + mito<sup>Ex</sup>), were included in the present study.</p><p><strong>Results: </strong><i>In vitro</i> study showed an abundance of mito<sup>Ex</sup> found in recipient-L2 cells, resulting in significantly higher mitochondrial-cytochrome-C, adenosine triphosphate and relative mitochondrial DNA levels (<i>P</i> < 0.001). The protein levels of inflammation [interleukin (IL)-1β/tumor necrosis factor (TNF)-α/nuclear factor-κB/toll-like receptor (TLR)-4/matrix-metalloproteinase (MMP)-9/oxidative-stress (NOX-1/NOX-2)/apoptosis (cleaved-caspase3/cleaved-poly (ADP-ribose) polymerase)] were significantly attenuated in lipopolysaccharide (LPS)-treated L2 cells with EX<sup>AD</sup> treatment than without EX<sup>AD</sup> treatment, whereas the protein expressions of cellular junctions [occluding/β-catenin/zonula occludens (ZO)-1/E-cadherin] exhibited an opposite pattern of inflammation (all <i>P</i> < 0.001). Animals were euthanized by 72 h post-48 h-ARDS induction, and lung tissues were harvested. By 72 h, flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflammatory cells (Ly6G+/CD14+/CD68+/CD11<sup>b/c</sup>+/myeloperoxidase+) and albumin were lowest in group 1, highest in group 2, and significantly higher in groups 3 and 4 than in group 5 (all <i>P</i> < 0.0001), whereas arterial oxygen-saturation (SaO<sub>2</sub>%) displayed an opposite pattern of albumin among the groups. Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers (CD68+/γ-H2AX) displayed an identical pattern of SaO<sub>2</sub>% among the groups (all <i>P</i> < 0.0001). The protein expressions of inflammatory (TLR-4/MMP-9/IL-1β/TNF-α)/oxidative stress (NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged (cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic (beclin-1/Atg-5/ratio of LC3B-II/LC3B-I) biomarkers exhibited a similar manner, whereas antioxidants [nuclear respiratory factor (Nrf)-1/Nrf-2]/cellular junctions (ZO-1/E-cadherin)/mitochondrial electron transport chain (complex I-V) exhibited an opposite manner of albumin among the groups (all <i>P</i> < 0.0001).</p><p><strong>Conclusion: </strong>Combined EX<sup>AD</sup>-mito<sup>Ex</sup> therapy was better than merely one for protecting the lu
{"title":"Outcomes of combined mitochondria and mesenchymal stem cells-derived exosome therapy in rat acute respiratory distress syndrome and sepsis.","authors":"Kun-Chen Lin, Wen-Feng Fang, Jui-Ning Yeh, John Y Chiang, Hsin-Ju Chiang, Pei-Lin Shao, Pei-Hsun Sung, Hon-Kan Yip","doi":"10.4252/wjsc.v16.i6.690","DOIUrl":"10.4252/wjsc.v16.i6.690","url":null,"abstract":"<p><strong>Background: </strong>The treatment of acute respiratory distress syndrome (ARDS) complicated by sepsis syndrome (SS) remains challenging.</p><p><strong>Aim: </strong>To investigate whether combined adipose-derived mesenchymal-stem-cells (ADMSCs)-derived exosome (EX<sup>AD</sup>) and exogenous mitochondria (mito<sup>Ex</sup>) protect the lung from ARDS complicated by SS.</p><p><strong>Methods: </strong><i>In vitro</i> study, including L2 cells treated with lipopolysaccharide (LPS) and <i>in vivo</i> study including male-adult-SD rats categorized into groups 1 (sham-operated-control), 2 (ARDS-SS), 3 (ARDS-SS + EX<sup>AD</sup>), 4 (ARDS-SS + mito<sup>Ex</sup>), and 5 (ARDS-SS + EX<sup>AD</sup> + mito<sup>Ex</sup>), were included in the present study.</p><p><strong>Results: </strong><i>In vitro</i> study showed an abundance of mito<sup>Ex</sup> found in recipient-L2 cells, resulting in significantly higher mitochondrial-cytochrome-C, adenosine triphosphate and relative mitochondrial DNA levels (<i>P</i> < 0.001). The protein levels of inflammation [interleukin (IL)-1β/tumor necrosis factor (TNF)-α/nuclear factor-κB/toll-like receptor (TLR)-4/matrix-metalloproteinase (MMP)-9/oxidative-stress (NOX-1/NOX-2)/apoptosis (cleaved-caspase3/cleaved-poly (ADP-ribose) polymerase)] were significantly attenuated in lipopolysaccharide (LPS)-treated L2 cells with EX<sup>AD</sup> treatment than without EX<sup>AD</sup> treatment, whereas the protein expressions of cellular junctions [occluding/β-catenin/zonula occludens (ZO)-1/E-cadherin] exhibited an opposite pattern of inflammation (all <i>P</i> < 0.001). Animals were euthanized by 72 h post-48 h-ARDS induction, and lung tissues were harvested. By 72 h, flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflammatory cells (Ly6G+/CD14+/CD68+/CD11<sup>b/c</sup>+/myeloperoxidase+) and albumin were lowest in group 1, highest in group 2, and significantly higher in groups 3 and 4 than in group 5 (all <i>P</i> < 0.0001), whereas arterial oxygen-saturation (SaO<sub>2</sub>%) displayed an opposite pattern of albumin among the groups. Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers (CD68+/γ-H2AX) displayed an identical pattern of SaO<sub>2</sub>% among the groups (all <i>P</i> < 0.0001). The protein expressions of inflammatory (TLR-4/MMP-9/IL-1β/TNF-α)/oxidative stress (NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged (cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic (beclin-1/Atg-5/ratio of LC3B-II/LC3B-I) biomarkers exhibited a similar manner, whereas antioxidants [nuclear respiratory factor (Nrf)-1/Nrf-2]/cellular junctions (ZO-1/E-cadherin)/mitochondrial electron transport chain (complex I-V) exhibited an opposite manner of albumin among the groups (all <i>P</i> < 0.0001).</p><p><strong>Conclusion: </strong>Combined EX<sup>AD</sup>-mito<sup>Ex</sup> therapy was better than merely one for protecting the lu","PeriodicalId":23775,"journal":{"name":"World journal of stem cells","volume":"16 6","pages":"690-707"},"PeriodicalIF":3.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The stem cell pre-treatment approaches at cellular and sub-cellular levels encompass physical manipulation of stem cells to growth factor treatment, genetic manipulation, and chemical and pharmacological treatment, each strategy having advantages and limitations. Most of these pre-treatment protocols are non-combinative. This editorial is a continuum of Li et al's published article and Wan et al's editorial focusing on the significance of pre-treatment strategies to enhance their stemness, immunoregulatory, and immunosuppressive properties. They have elaborated on the intricacies of the combinative pre-treatment protocol using pro-inflammatory cytokines and hypoxia. Applying a well-defined multi-pronged combinatorial strategy of mesenchymal stem cells (MSCs), pre-treatment based on the mechanistic understanding is expected to develop "Super MSCs", which will create a transformative shift in MSC-based therapies in clinical settings, potentially revolutionizing the field. Once optimized, the standardized protocols may be used with slight modifications to pre-treat different stem cells to develop "super stem cells" with augmented stemness, functionality, and reparability for diverse clinical applications with better outcomes.
{"title":"Priming mesenchymal stem cells to develop \"super stem cells\".","authors":"Khawaja Husnain Haider","doi":"10.4252/wjsc.v16.i6.623","DOIUrl":"10.4252/wjsc.v16.i6.623","url":null,"abstract":"<p><p>The stem cell pre-treatment approaches at cellular and sub-cellular levels encompass physical manipulation of stem cells to growth factor treatment, genetic manipulation, and chemical and pharmacological treatment, each strategy having advantages and limitations. Most of these pre-treatment protocols are non-combinative. This editorial is a continuum of Li <i>et al</i>'s published article and Wan <i>et al</i>'s editorial focusing on the significance of pre-treatment strategies to enhance their stemness, immunoregulatory, and immunosuppressive properties. They have elaborated on the intricacies of the combinative pre-treatment protocol using pro-inflammatory cytokines and hypoxia. Applying a well-defined multi-pronged combinatorial strategy of mesenchymal stem cells (MSCs), pre-treatment based on the mechanistic understanding is expected to develop \"Super MSCs\", which will create a transformative shift in MSC-based therapies in clinical settings, potentially revolutionizing the field. Once optimized, the standardized protocols may be used with slight modifications to pre-treat different stem cells to develop \"super stem cells\" with augmented stemness, functionality, and reparability for diverse clinical applications with better outcomes.</p>","PeriodicalId":23775,"journal":{"name":"World journal of stem cells","volume":"16 6","pages":"623-640"},"PeriodicalIF":3.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daniel B Ferreira, Leticia M Gasparoni, Cristiane F Bronzeri, Katiucia B S Paiva
Background: Validation of the reference gene (RG) stability during experimental analyses is essential for correct quantitative real-time polymerase chain reaction (RT-qPCR) data normalisation. Commonly, in an unreliable way, several studies use genes involved in essential cellular functions [glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 18S rRNA, and β-actin] without paying attention to whether they are suitable for such experimental conditions or the reason for choosing such genes. Furthermore, such studies use only one gene when Minimum Information for Publication of Quantitative Real-Time PCR Experiments guidelines recommend two or more genes. It impacts the credibility of these studies and causes distortions in the gene expression findings. For tissue engineering, the accuracy of gene expression drives the best experimental or therapeutical approaches.
Aim: To verify the most stable RG during osteogenic differentiation of human dental pulp stem cells (DPSCs) by RT-qPCR.
Methods: We cultivated DPSCs under two conditions: Undifferentiated and osteogenic differentiation, both for 35 d. We evaluated the gene expression of 10 candidates for RGs [ribosomal protein, large, P0 (RPLP0), TATA-binding protein (TBP), GAPDH, actin beta (ACTB), tubulin (TUB), aminolevulinic acid synthase 1 (ALAS1), tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta (YWHAZ), eukaryotic translational elongation factor 1 alpha (EF1a), succinate dehydrogenase complex, subunit A, flavoprotein (SDHA), and beta-2-microglobulin (B2M)] every 7 d (1, 7, 14, 21, 28, and 35 d) by RT-qPCR. The data were analysed by the four main algorithms, ΔCt method, geNorm, NormFinder, and BestKeeper and ranked by the RefFinder method. We subdivided the samples into eight subgroups.
Results: All of the data sets from clonogenic and osteogenic samples were analysed using the RefFinder algorithm. The final ranking showed RPLP0/TBP as the two most stable RGs and TUB/B2M as the two least stable RGs. Either the ΔCt method or NormFinder analysis showed TBP/RPLP0 as the two most stable genes. However, geNorm analysis showed RPLP0/EF1α in the first place. These algorithms' two least stable RGs were B2M/GAPDH. For BestKeeper, ALAS1 was ranked as the most stable RG, and SDHA as the least stable RG. The pair RPLP0/TBP was detected in most subgroups as the most stable RGs, following the RefFinfer ranking.
Conclusion: For the first time, we show that RPLP0/TBP are the most stable RGs, whereas TUB/B2M are unstable RGs for long-term osteogenic differentiation of human DPSCs in traditional monolayers.
{"title":"RPLP0/TBP are the most stable reference genes for human dental pulp stem cells under osteogenic differentiation.","authors":"Daniel B Ferreira, Leticia M Gasparoni, Cristiane F Bronzeri, Katiucia B S Paiva","doi":"10.4252/wjsc.v16.i6.656","DOIUrl":"10.4252/wjsc.v16.i6.656","url":null,"abstract":"<p><strong>Background: </strong>Validation of the reference gene (RG) stability during experimental analyses is essential for correct quantitative real-time polymerase chain reaction (RT-qPCR) data normalisation. Commonly, in an unreliable way, several studies use genes involved in essential cellular functions [glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 18S rRNA, and β-actin] without paying attention to whether they are suitable for such experimental conditions or the reason for choosing such genes. Furthermore, such studies use only one gene when Minimum Information for Publication of Quantitative Real-Time PCR Experiments guidelines recommend two or more genes. It impacts the credibility of these studies and causes distortions in the gene expression findings. For tissue engineering, the accuracy of gene expression drives the best experimental or therapeutical approaches.</p><p><strong>Aim: </strong>To verify the most stable RG during osteogenic differentiation of human dental pulp stem cells (DPSCs) by RT-qPCR.</p><p><strong>Methods: </strong>We cultivated DPSCs under two conditions: Undifferentiated and osteogenic differentiation, both for 35 d. We evaluated the gene expression of 10 candidates for RGs [ribosomal protein, large, P0 (<i>RPLP0</i>), TATA-binding protein (<i>TBP</i>), <i>GAPDH</i>, actin beta (<i>ACTB</i>), tubulin (<i>TUB</i>), aminolevulinic acid synthase 1 (<i>ALAS1</i>), tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta (<i>YWHAZ</i>), eukaryotic translational elongation factor 1 alpha (<i>EF1a</i>), succinate dehydrogenase complex, subunit A, flavoprotein (<i>SDHA</i>), and beta-2-microglobulin (<i>B2M</i>)] every 7 d (1, 7, 14, 21, 28, and 35 d) by RT-qPCR. The data were analysed by the four main algorithms, ΔCt method, geNorm, NormFinder, and BestKeeper and ranked by the RefFinder method. We subdivided the samples into eight subgroups.</p><p><strong>Results: </strong>All of the data sets from clonogenic and osteogenic samples were analysed using the RefFinder algorithm. The final ranking showed RPLP0/TBP as the two most stable RGs and TUB/B2M as the two least stable RGs. Either the ΔCt method or NormFinder analysis showed TBP/RPLP0 as the two most stable genes. However, geNorm analysis showed RPLP0/EF1α in the first place. These algorithms' two least stable RGs were B2M/GAPDH. For BestKeeper, ALAS1 was ranked as the most stable RG, and SDHA as the least stable RG. The pair RPLP0/TBP was detected in most subgroups as the most stable RGs, following the RefFinfer ranking.</p><p><strong>Conclusion: </strong>For the first time, we show that RPLP0/TBP are the most stable RGs, whereas TUB/B2M are unstable RGs for long-term osteogenic differentiation of human DPSCs in traditional monolayers.</p>","PeriodicalId":23775,"journal":{"name":"World journal of stem cells","volume":"16 6","pages":"656-669"},"PeriodicalIF":3.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Edoardo Agosti, Marco Zeppieri, Mattia Ghidoni, Tamara Ius, Alessandro Tel, Marco Maria Fontanella, Pier Paolo Panciani
<p><strong>Background: </strong>Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy. Glioma stem cells (GSCs), a subset within tumors, contribute to resistance, tumor heterogeneity, and plasticity. Recent studies reveal GSCs' role in therapeutic resistance, driven by DNA repair mechanisms and dynamic transitions between cellular states. Resistance mechanisms can involve different cellular pathways, most of which have been recently reported in the literature. Despite progress, targeted therapeutic approaches lack consensus due to GSCs' high plasticity.</p><p><strong>Aim: </strong>To analyze targeted therapies against GSC-mediated resistance to radio- and chemotherapy in gliomas, focusing on underlying mechanisms.</p><p><strong>Methods: </strong>A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to September 30, 2023. The search strategy utilized relevant Medical Subject Heading terms and keywords related to including "glioma stem cells", "radiotherapy", "chemotherapy", "resistance", and "targeted therapies". Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated resistance to radiotherapy resistance (RTR).</p><p><strong>Results: </strong>In a comprehensive review of 66 studies on stem cell therapies for SCI, 452 papers were initially identified, with 203 chosen for full-text analysis. Among them, 201 were deemed eligible after excluding 168 for various reasons. The temporal breakdown of studies illustrates this trend: 2005-2010 (33.3%), 2011-2015 (36.4%), and 2016-2022 (30.3%). Key GSC models, particularly U87 (33.3%), U251 (15.2%), and T98G (15.2%), emerge as significant in research, reflecting their representativeness of glioma characteristics. Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) (27.3%) and Notch (12.1%) pathways, suggesting their crucial roles in resistance development. Targeted molecules with mTOR (18.2%), CHK1/2 (15.2%), and ATP binding cassette G2 (12.1%) as frequent targets underscore their importance in overcoming GSC-mediated resistance. Various therapeutic agents, notably RNA inhibitor/short hairpin RNA (27.3%), inhibitors (<i>e.g.,</i> LY294002, NVP-BEZ235) (24.2%), and monoclonal antibodies (<i>e.g.,</i> cetuximab) (9.1%), demonstrate versatility in targeted therapies. among 20 studies (60.6%), the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance (51.5%), followed by reductions in carmustine resistance (9.1%) and doxorubicin resistance (3.0%), while resistance to RTR is reduced in 42.4% of studies.</p><p><strong>Conclusion: </strong>GSCs play a complex role in mediating radioresistance and chemoresistance, emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population an
{"title":"Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments.","authors":"Edoardo Agosti, Marco Zeppieri, Mattia Ghidoni, Tamara Ius, Alessandro Tel, Marco Maria Fontanella, Pier Paolo Panciani","doi":"10.4252/wjsc.v16.i5.604","DOIUrl":"10.4252/wjsc.v16.i5.604","url":null,"abstract":"<p><strong>Background: </strong>Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy. Glioma stem cells (GSCs), a subset within tumors, contribute to resistance, tumor heterogeneity, and plasticity. Recent studies reveal GSCs' role in therapeutic resistance, driven by DNA repair mechanisms and dynamic transitions between cellular states. Resistance mechanisms can involve different cellular pathways, most of which have been recently reported in the literature. Despite progress, targeted therapeutic approaches lack consensus due to GSCs' high plasticity.</p><p><strong>Aim: </strong>To analyze targeted therapies against GSC-mediated resistance to radio- and chemotherapy in gliomas, focusing on underlying mechanisms.</p><p><strong>Methods: </strong>A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to September 30, 2023. The search strategy utilized relevant Medical Subject Heading terms and keywords related to including \"glioma stem cells\", \"radiotherapy\", \"chemotherapy\", \"resistance\", and \"targeted therapies\". Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated resistance to radiotherapy resistance (RTR).</p><p><strong>Results: </strong>In a comprehensive review of 66 studies on stem cell therapies for SCI, 452 papers were initially identified, with 203 chosen for full-text analysis. Among them, 201 were deemed eligible after excluding 168 for various reasons. The temporal breakdown of studies illustrates this trend: 2005-2010 (33.3%), 2011-2015 (36.4%), and 2016-2022 (30.3%). Key GSC models, particularly U87 (33.3%), U251 (15.2%), and T98G (15.2%), emerge as significant in research, reflecting their representativeness of glioma characteristics. Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) (27.3%) and Notch (12.1%) pathways, suggesting their crucial roles in resistance development. Targeted molecules with mTOR (18.2%), CHK1/2 (15.2%), and ATP binding cassette G2 (12.1%) as frequent targets underscore their importance in overcoming GSC-mediated resistance. Various therapeutic agents, notably RNA inhibitor/short hairpin RNA (27.3%), inhibitors (<i>e.g.,</i> LY294002, NVP-BEZ235) (24.2%), and monoclonal antibodies (<i>e.g.,</i> cetuximab) (9.1%), demonstrate versatility in targeted therapies. among 20 studies (60.6%), the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance (51.5%), followed by reductions in carmustine resistance (9.1%) and doxorubicin resistance (3.0%), while resistance to RTR is reduced in 42.4% of studies.</p><p><strong>Conclusion: </strong>GSCs play a complex role in mediating radioresistance and chemoresistance, emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population an","PeriodicalId":23775,"journal":{"name":"World journal of stem cells","volume":"16 5","pages":"604-614"},"PeriodicalIF":4.1,"publicationDate":"2024-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11135247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}