Abstract:
:: Phosphatase and tension homolog (PTEN) is a widely known negative regulator of insulin/phosphatidylinositol 3-kinase (PI3K) signaling. The PI3K/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) and Ras-extracellular signal-regulated kinase (Ras-ERK) signaling pathways are the chief mechanisms controlling the survival, proliferation, and differentiation of neural stem cells (NSCs). However, the roles of PTEN in Akt/mTOR and ERK signaling during proliferation and neuronal differentiation of human NSCs (hNSCs) are poorly understood. Treatment of proliferating hNSCs with a specific inhibitor of PTEN or overexpression of the PTEN inactive mutant G129E resulted in an increase in the expression levels of Ki67, p-S6 kinase (p-S6K), and p-ERK without affecting p-Akt expression during proliferation of hNSCs. Therefore, we focused on the regulatory effect of PTEN in S6K and ERK signaling during dopaminergic neuronal differentiation of hNSCs. Overexpression of PTEN during neuronal differentiation of hNSCs caused an increase in p-S6K expression and a decrease in p-ERK expression. Conversely, inhibition of PTEN increased p-ERK expression and decreased p-S6K expression. Inhibition of ERK by a specific chemical inhibitor, U0126, promoted neuronal generation, especially of tyrosine hydroxylase-positive neurons. p-S6K expression increased in a time-dependent manner during differentiation, and this effect was enhanced by U0126. These results indicated that PTEN promoted neuronal differentiation by inhibition of ERK signaling, which in turn induced activation of S6K. Our data suggest that ERK pathways participate in crosstalk with S6K through PTEN signaling during neuronal differentiation of hNSCs. These results represent a novel pathway by which PTEN may modulate the interplay between ERK and S6K signaling, leading to increased neuronal differentiation in hNSCs. SIGNIFICANCE:This article adds to the body of knowledge about the mechanism of extracellular signal-regulated kinase (ERK)-mediated differentiation by describing the molecular function of phosphatase and tension homolog (PTEN) during the neuronal differentiation of human neural stem cells (hNSCs). Previous studies showed that S6K signaling promoted neuronal differentiation in hNSCs via the phosphatidylinositol 3-kinase Akt-mammalian target of rapamycin signaling pathway. A further series of studies investigated whether this S6 kinase-induced differentiation in hNSCs involves regulation of ERK signaling by PTEN. The current study identified a novel mechanism by which PTEN regulates neuronal differentiation in hNSCs, suggesting that activating PTEN function promotes dopaminergic neuronal differentiation and providing an important resource for future studies of PTEN function.
journal_name
Stem Cells Transl Medjournal_title
Stem cells translational medicineauthors
Lee JE,Lim MS,Park JH,Park CH,Koh HCdoi
10.5966/sctm.2015-0200subject
Has Abstractpub_date
2016-10-01 00:00:00pages
1319-1329issue
10eissn
2157-6564issn
2157-6580pii
sctm.2015-0200journal_volume
5pub_type
杂志文章abstract::Although mesenchymal stromal cells (MSCs) possess immunomodulatory properties and exhibit promising efficacy against chronic graft-versus-host disease (cGVHD), little is known about the immune changes by which MSCs ameliorate cGVHD in vivo. Recent studies have suggested that B lymphocytes might play an important role ...
journal_title:Stem cells translational medicine
pub_type: 临床试验,杂志文章
doi:10.5966/sctm.2014-0001
更新日期:2014-09-01 00:00:00
abstract:BACKGROUND:Tendon or ligament tears can decrease patients' quality of life. Many therapeutic interventions are available to treat such injuries. Mesenchymal stem cells (MSCs) have been shown to be effective in treating tendon or ligament tears; however, the use of stem cell-conditioned medium (CM) requires further inve...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.19-0388
更新日期:2020-08-01 00:00:00
abstract::The potential plasticity and therapeutic utility in tissue regeneration of human adipose-derived stem cells (ASCs) isolated from adult adipose tissue have recently been highlighted. The use of autologous platelet-rich plasma (PRP) represents an alternative strategy in regenerative medicine for the local release of mul...
journal_title:Stem cells translational medicine
pub_type: 杂志文章,随机对照试验
doi:10.5966/sctm.2011-0052
更新日期:2012-03-01 00:00:00
abstract::Patient-specific induced pluripotent stem cells (iPSCs) hold great promise for many applications, including disease modeling to elucidate mechanisms involved in disease pathogenesis, drug screening, and ultimately regenerative medicine therapies. A frequently used starting source of cells for reprogramming has been de...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2014-0121
更新日期:2014-12-01 00:00:00
abstract::Cardiovascular disease is a major cause of morbidity and mortality, especially in developed countries. Various therapies for cardiovascular disease are investigated actively and are performed clinically. Recently, cell-based regenerative medicine using several cell sources has appeared as an alternative therapy for cu...
journal_title:Stem cells translational medicine
pub_type: 杂志文章,评审
doi:10.5966/sctm.2012-0030
更新日期:2012-02-01 00:00:00
abstract::Mesenchymal stem cells (multipotent stromal cells; MSCs) have been under investigation for the treatment of diverse diseases, with many promising outcomes achieved in animal models and clinical trials. The biological activity of MSC therapies has not been fully resolved which is critical to rationalizing their use and...
journal_title:Stem cells translational medicine
pub_type: 杂志文章,评审
doi:10.1002/sctm.19-0446
更新日期:2020-09-01 00:00:00
abstract::γδT cells constitute a small proportion of lymphocytes in peripheral blood. Unlike αβT cells, the anti-tumor activities are exerted through several different pathways in a MHC-unrestricted manner. Thus, immunotherapy using γδT cells is considered to be effective for various types of cancer. Occasionally, however, ex v...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.17-0021
更新日期:2018-01-01 00:00:00
abstract::Perivascular stem cells (PSCs) are the natural ancestors of mesenchymal stem cells (MSCs) and are the stem cells responsible for homeostasis and repair in vivo. Prospectively identified and isolated PSCs have demonstrated increased plasticity and osteogenic potential. Cells from the infrapatellar fat pad (IFP) have de...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2016-0040
更新日期:2017-01-01 00:00:00
abstract::Cancer stem cells (CSCs) are a subpopulation of tumor cells that have strong self-renewal capabilities and may contribute to the failure of conventional cancer therapies. Hence, therapeutics homing in on CSCs represent a novel and promising approach that may eradicate malignant tumors. However, the lack of information...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2015-0289
更新日期:2017-02-01 00:00:00
abstract::Global cerebral ischemia (GCI) is the leading cause of a poor prognosis even after successful resuscitation from cardiac arrest. Therapeutic induction of hypothermia (TH) is the only proven therapy-and current standard care-for GCI after cardiac arrest; however, its application has been significantly limited owing to ...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2014-0103
更新日期:2015-02-01 00:00:00
abstract::Adipose-derived stem cell (ADSC)-based therapy is promising for critical limb ischemia (CLI) treatment, especially in patients with diabetes. However, the therapeutic effects of diabetic ADSCs (D-ADSCs) are impaired by the diabetes, possibly through intracellular reactive oxygen species (ROS) accumulation. The objecti...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2015-0380
更新日期:2017-01-01 00:00:00
abstract::Generation of desired cell types by cell conversion remains a challenge. In particular, derivation of novel cell subtypes identified by single-cell technologies will open up new strategies for cell therapies. The recent increase in the generation of single-cell RNA-sequencing (scRNA-seq) data and the concomitant incre...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.20-0227
更新日期:2021-02-01 00:00:00
abstract::We conducted a phase II, noncomparative, multicenter study to assess the efficacy and safety of allogeneic bone marrow-derived mesenchymal stromal cells (BM-MSCs) expanded in vitro for patients with aplastic anemia (AA) refractory to immunosuppressive therapy. Seventy-four patients from seven centers received allogene...
journal_title:Stem cells translational medicine
pub_type: 杂志文章,多中心研究
doi:10.1002/sctm.16-0227
更新日期:2017-07-01 00:00:00
abstract::Niemann-Pick disease, type C1 (NPC1) is a familial disorder that has devastating consequences on postnatal development with multisystem effects, including neurodegeneration. There is no Food and Drug Administration-approved treatment option for NPC1; however, several potentially therapeutic compounds have been identif...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2014-0127
更新日期:2015-03-01 00:00:00
abstract::The potential of autologous cell-based therapies including those using multipotent mesenchymal stromal cells (MSCs) is being investigated for multiple sclerosis (MS) and other neurological conditions. However, the phenotype of MSC in neurological diseases has not been fully characterized. We have previously shown that...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.18-0045
更新日期:2018-10-01 00:00:00
abstract::An important stage in the development of any new therapeutic agent is establishment of the optimal dosage and route of administration. This can be particularly challenging when the treatment is a biologic agent that might exert its therapeutic effects via complex or poorly understood mechanisms. Multiple preclinical a...
journal_title:Stem cells translational medicine
pub_type: 杂志文章,评审
doi:10.5966/sctm.2015-0101
更新日期:2016-02-01 00:00:00
abstract::Diabetes is a major global health issue and the number of individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D) increases annually across multiple populations. Research to develop a cure must overcome multiple immune dysfunctions and the shortage of pancreatic islet β cells, but these challenges have proven...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.17-0078
更新日期:2017-08-01 00:00:00
abstract::Basic and translational research on lung biology has discovered multiple progenitor cell types, specialized or facultative, responsible for turnover, renewal, and repair. Isolation of populations of resident lung progenitor cells (LPCs) has been described by multiple protocols, and some have been successfully applied ...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2015-0374
更新日期:2017-03-01 00:00:00
abstract::In the field of disease modeling, induced pluripotent stem cells (iPSCs) have become an appealing choice, especially for diseases that do not have an animal model. They can be generated from patients with known clinical features and compared with cells from healthy controls to identify the biological bases of disease....
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2012-0043
更新日期:2012-09-01 00:00:00
abstract::Improved therapeutic assessment of experimental traumatic brain injury (TBI), using mesenchymal stem cells (MSCs), would immensely benefit its therapeutic management. Neurometabolite patterns at injury site, measured with proton magnetic resonance spectroscopy (1H-MRS) after MSCs transplantation, may serve as a bio-in...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2016-0087
更新日期:2017-01-01 00:00:00
abstract::An understanding of how cancer cells adapt dormancy would allow for targeted treatment. The current literature suggests that the cancer stem cells might be the major cells with the ability to become quiescent and to resist current drug treatment. The properties of cancer stem cells and healthy stem cells are functiona...
journal_title:Stem cells translational medicine
pub_type: 杂志文章,评审
doi:10.5966/sctm.2014-0013
更新日期:2014-07-01 00:00:00
abstract:UNLABELLED:: Present therapies for stroke rest with tissue plasminogen activator (tPA), the sole licensed antithrombotic on the market; however, tPA's effectiveness is limited in that the drug not only must be administered less than 3-5 hours after stroke but often exacerbates blood-brain barrier (BBB) leakage and incr...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2014-0184
更新日期:2015-07-01 00:00:00
abstract::Osteoarthritis (OA) remains an intractable clinical challenge. Few drugs are available for reversing this degenerative disease, although some promising candidates have performed well in preclinical studies. Tumor necrosis factor α (TNFα) has been identified as a crucial effector modulating OA pathogenesis. This study ...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2014-0200
更新日期:2015-05-01 00:00:00
abstract::Peripheral nerve injury presents significant therapeutic challenges for recovery of motor and sensory function in patients. Different clinical approaches exist but to date there has been no consensus on the most effective method of treatment. Here, we investigate a novel approach to peripheral nerve repair using olfac...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.16-0420
更新日期:2017-10-01 00:00:00
abstract::Development of efficient and reproducible conditions for directed differentiation of pluripotent stem cells into specific cell types is important not only to understand early human development but also to enable more practical applications, such as in vitro disease modeling, drug discovery, and cell therapies. The dif...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2016-0088
更新日期:2017-02-01 00:00:00
abstract::Animal models show that systemically administered bone marrow-derived mesenchymal stem cells (MSCs) home to sites of primary and metastatic prostate cancer (PC)-making them candidates to selectively deliver cytotoxic agents. To further assess this potential as a cell-based therapeutic vehicle, a phase I study testing ...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.18-0230
更新日期:2019-05-01 00:00:00
abstract::Cell-based therapies have gained interest as a potential treatment method in cardiovascular disease in the past two decades, peripheral artery disease amongst others. Initial pre-clinical and small pilot clinical studies showed promising effects of cell therapy in peripheral artery disease and chronic limb-threatening...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.18-0025
更新日期:2018-12-01 00:00:00
abstract::Bone marrow mesenchymal stem cells (BMSCs) have been shown to offer a wide variety of cellular functions including the protective effects on damaged hearts. Here we investigated the antiaging properties of BMSCs and the underlying mechanism in a cellular model of cardiomyocyte senescence and a rat model of aging heart...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2014-0206
更新日期:2015-05-01 00:00:00
abstract::Gaucher disease, the most prevalent metabolic storage disorder, is caused by mutations in the glucocerebrosidase gene GBA1, which lead to the accumulation of glucosylceramide (GlcCer) in affected cells. Gaucher disease type 1 (GD1), although defined as nonneuronopathic subtype, is accompanied by an increased risk of P...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.20-0302
更新日期:2020-12-20 00:00:00
abstract:UNLABELLED:The California Institute for Regenerative Medicine (CIRM) has invested approximately $70 million in programs targeting various orthopedic indications, including osteoporosis, bone fracture healing, vertebral compression fractures, and several others. The present article serves to outline the current state of...
journal_title:Stem cells translational medicine
pub_type: 杂志文章,评审
doi:10.5966/sctm.2015-0202
更新日期:2015-11-01 00:00:00