Electroacupuncture Ameliorates Depression-Like Behaviors Comorbid to Chronic Neuropathic Pain via Tet1-Mediated Restoration of Adult Neurogenesis.

Although electroacupuncture (EA) stimulation is a widely used therapy for chronic pain and comorbid psychiatric disorders, its long-term effects on chronic neuropathic pain-induced depression and the underlying mechanisms remain elusive. In the present study, we found that EA stimulation was able to restore adult neurogenesis in the ventral dentate gyrus (DG), by both increasing neuronal differentiation and restoring the normal morphology of newborn dendrites, in mice with spared nerve injury surgery. By ablating the Nestin+ neural stem cells (NSCs) via diphtheria toxin fragment A expression, we further proved that neurogenesis in the ventral DG was crucial to the long-term, but not the immediate antidepressant effect of EA, nor was it associated with nociception. Furthermore, we found that the restoration of neurogenesis was dependent on Tet1-mediated epigenetic modification upon EA treatment. Tet1 could bind to the promoter of the Prox1 gene, thus catalyzing its demethylation and facilitating its expression, which finally contributed to the restoration of neurogenesis and amelioration of depression-like behaviors induced by chronic neuropathic pain. Thus, we conclude that EA stimulation restores inhibited Tet1 expression in hippocampal NSCs of mice with chronic neuropathic pain, and increased Tet1 expression ameliorates hypermethylation of Prox1 and restores normal adult neurogenesis in the ventral DG, which contributes to the long-term antidepressant effect of EA.

Adult stem cell transplantation combined with conventional therapy for the treatment of end-stage liver disease: a systematic review and meta-analysis.

End-stage liver disease (ESLD) is characterized by the deterioration of liver function and a subsequent high mortality rate. Studies have investigated the use of adult stem cells to treat ESLD. Here, a systematic review and meta-analysis was conducted to determine the efficacy of a combination therapy with adult stem cell transplantation and traditional medicine for treating ESLD. Four databases-including PubMed, Web of Science, Embase, and Cochrane Library-were investigated for studies published before January 31, 2021. The main outcome indicators were liver function index, model for end-stage liver disease (MELD) scores, and Child‒Turcotte‒Pugh (CTP) scores. Altogether, 1604 articles were retrieved, of which eight met the eligibility criteria; these studies included data for 579 patients with ESLD. Combination of adult stem cell transplantation with conventional medicine significantly improved its efficacy with respect to liver function index, CTP and MELD scores, but this effect gradually decreased over time. Moreover, a single injection of stem cells was more effective than two injections with respect to MELD and CTP scores and total bilirubin (TBIL) and albumin (ALB) levels, with no significant difference in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. With respect to the TBIL levels, patients receiving mononuclear cells (MNCs) experienced a significantly greater therapeutic effect-starting from twenty-four weeks after the treatment-whereas with respect to ALB levels, CD34+ autologous peripheral blood stem cells (CD34+ APBSCs) and MNCs had similar therapeutic effects. Severe complications associated with adult stem cell treatment were not observed. Although the benefits of combination therapy with respect to improving liver function were slightly better than those of the traditional treatment alone, they gradually decreased over time.Systematic review registration: PROSPERO registration number: CRD42021238576.

Cartilage tissue formation from human adipose-derived stem cells via herbal component (Avocado/soybean unsaponifiables) in scaffold-free culture system.

BACKGROUND: The use of stem cells, growth factors, and scaffolds to repair damaged tissues is a new idea in tissue engineering. The aim of the present study is the investigation of Avocado/soybean (A/S) effects on chondrogenic differentiation of human adipose-derived stem cells (hADSCs) in micromass culture to access cartilage tissue with high quality. MATERIALS AND METHODS: In this an experimental study After hADSCs characterization, chondrogenic differentiation was induced using transforming growth factor beta 1 (TGF-ß1) (10 ng/ml) and different concentrations (5, 10, and 20 µg/ml) of A/S in micromass culture. The efficiency of A/S on specific gene expression (types I, II, and X collagens, SOX9, and aggrecan) was evaluated using quantitative polymerase chain reaction. In addition, histological study was done using hematoxylin and eosin and toluidine blue staining all data were analyzed using one-way analysis of variance (ANOVA) and P ≤ 0.05 was considered to be statistically significant. RESULTS: The results of this study indicated that A/S can promote chondrogenic differentiation in a dose-dependent manner. In particular, 5 ng/ml A/S showed the highest expression of type II collagen, SOX9, and aggrecan which are effective and important markers in chondrogenic differentiation. In addition, the expression of types I and X collagens which are hypertrophic and fibrous factors in chondrogenesis is lower in present of 5 ng/ml A/S compared with TGF-ß1 group (P ≤ 0.05). Moreover, the sulfated glycosaminoglycans in the extracellular matrix and the presence of chondrocytes within lacuna were more prominent in 5 ng/ml A/S group than other groups. CONCLUSION: It can be concluded that A/S similar to TGF-ß1 is able to facilitate the chondrogenic differentiation of hADSCs and do not have adverse effects of TGF-ß1. Thus, TGF-ß1 can be replaced by A/S in the field of tissue engineering.

WNT Takes Two to Tango: Molecular Links between the Circadian Clock and the Cell Cycle in Adult Stem Cells.

Like two dancers, the circadian clock and cell cycle are biological oscillators engaged in bidirectional communication, resulting in circadian clock-gated cell division cycles in species ranging from cyanobacteria to mammals. The identified mechanisms for this phenomenon have expanded beyond intracellular molecular coupling components to include intercellular connections. However, detailed molecular mechanisms, dynamics, and physiological functions of the circadian clock and cell cycle as coupled oscillators remain largely unknown. In this review, we discuss current understanding of this connection in light of recent findings that have uncovered intercellular coupling between the circadian clock in Paneth cells and the cell cycle in intestinal stem cells via WNT signaling. This extends the impact of circadian rhythms regulating the timing of cell divisions beyond the intracellular domain of homogenous cell populations into dynamic, multicellular systems. In-depth understanding of the molecular links and dynamics of these two oscillators will identify potential targets and temporal regimens for effective chronotherapy.

Electroacupuncture Promotes Central Nervous System-Dependent Release of Mesenchymal Stem Cells.

Electroacupuncture (EA) performed in rats and humans using limb acupuncture sites, LI-4 and LI-11, and GV-14 and GV-20 (humans) and Bai-hui (rats) increased functional connectivity between the anterior hypothalamus and the amygdala and mobilized mesenchymal stem cells (MSCs) into the systemic circulation. In human subjects, the source of the MSC was found to be primarily adipose tissue, whereas in rodents the tissue sources were considered more heterogeneous. Pharmacological disinhibition of rat hypothalamus enhanced sympathetic nervous system (SNS) activation and similarly resulted in a release of MSC into the circulation. EA-mediated SNS activation was further supported by browning of white adipose tissue in rats. EA treatment of rats undergoing partial rupture of the Achilles tendon resulted in reduced mechanical hyperalgesia, increased serum interleukin-10 levels and tendon remodeling, effects blocked in propranolol-treated rodents. To distinguish the afferent role of the peripheral nervous system, phosphoinositide-interacting regulator of transient receptor potential channels (Pirt)-GCaMP3 (genetically encoded calcium sensor) mice were treated with EA acupuncture points, ST-36 and LIV-3, and GV-14 and Bai-hui and resulted in a rapid activation of primary sensory neurons. EA activated sensory ganglia and SNS centers to mediate the release of MSC that can enhance tissue repair, increase anti-inflammatory cytokine production and provide pronounced analgesic relief. Stem Cells 2017;35:1303-1315.

Apple ethanol extract promotes proliferation of human adult stem cells, which involves the regenerative potential of stem cells.

Tissue regeneration using adult stem cells (ASCs) has significant potential as a novel treatment for many degenerative diseases. Previous studies have established that age negatively affects the proliferation status and differentiation potential of ASCs, suggesting a possible limitation in their potential therapeutic use. Therefore, we hypothesized that apple extract might exert beneficial effects on ASCs. The specific objectives were to investigate the proliferative effect of apple ethanol extract on human adipose tissue-derived mesenchymal stem cells (ADSCs) and human cord blood-derived mesenchymal stem cells (CB-MSCs), and identify the possible molecular mechanisms. Apple extract promoted proliferation of ADSCs and CB-MSCs as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Click-iT 5-ethynyl-2'-deoxyuridine flow cytometry assays. In addition, phosphorylation of p44/42 MAPK (ERK), mammalian target of rapamycin (mTOR), p70 S6 kinase (p70S6K), S6 ribosomal protein (S6RP), eukaryotic initiation factor (eIF) 4B and eIF4E was induced stepwise in ADSCs. Furthermore, apple extract significantly induced the production of vascular endothelial growth factor and interleukin-6 in both ADSCs and CB-MSCs. Similarly, apple extract-induced phosphorylation of the mTOR/p70S6K/S6RP/eIF4B/eIF4E pathway was blocked by pretreatment with PD98059, a specific ERK inhibitor. These results indicate that apple extract-induced proliferation of ADSCs under serum-free conditions is mediated by ERK-dependent cytokine production. Moreover, the beneficial effect of apple extract on proliferation of ASCs may overcome the limitation in therapeutic use of stem cells in tissue regeneration and maintenance of stem cell homeostasis.

The Yin and Yang of Chromatin Dynamics In Stem Cell Fate Selection.

Adult organisms rely on tissue stem cells for maintenance and repair. During homeostasis, the concerted action of local niche signals and epigenetic regulators establish stable gene expression patterns to ensure that stem cells are not lost over time. However, stem cells also provide host tissues with a remarkable plasticity to respond to perturbations. How adult stem cells choose and acquire new fates is unknown, but the genome-wide mapping of epigenetic landscapes suggests a critical role for chromatin remodeling in these processes. Here, we explore the emerging role of chromatin modifiers and pioneer transcription factors in adult stem cell fate decisions and plasticity, which ensure that selective lineage choices are only made when environmentally cued.

Effect of traditional Chinese medicine three seven three alcohol saponinon on brain ischemic tolerance and proliferation of endogenous neural stem cells in rat / 中华老年医学杂志

Objective To investigate the effect of brain ischemic preconditioning (IP) combined with traditional Chinese medicine three seven three alcohol saponin (PTS) on proliferation of endogenous neural stem cells and the mRNA expressions of delta opioid receptor (DOR),Bax,Bcl-2 in hippocampus at 7d post middle cerebral artery occlusion (MCAO).Methods The focal-focal ischemic tolerance models were established with twice suture method.80 SD rats were included and randomly divided into 5 groups:sham group,MCAO group,sham+ MCAO group,IP+ MCAO group,PTS+MCAO group (n=16 each).We chose 10 SD rats from each group to evaluate their neurological status,and made BrdU fluorescent immunolabeling.In addition,we chose the other 6 SD rats to detect the expression levels of DOR,Bax and Bcl-2 mRNA in ischemic region in hippocampusby using RT-PCR.Animals were given one set of BrdU injections (on day 6,three times,4h apart,50mg/kg) to label the proliferating cells.The neurological status was assessed by using Zea Longa neurological deficit scores at 7 days following cerebral infarction.Results Zea longa neurologic deficit scores in MCAO group and sham+ MCAO) group had significantly differences with IP+ MCAO group and PTS+ MCAO group respectively at 7d post MCAO(P＜0.01).There was no significant differeuce in Zea-longa neurologic deficit scores between MCAO group versus sham+ MCAO group,and IP+ MCAO group versus PTS+ MCAO group(P＞0.05).The number of BrdU+ ceils in hippocampus had significant differences between IP+ MCAO and PTS+ MCAO groups at 7d post MCAOand three groups of sham,MCAO and sham+ MCAO respectively (P＜0.01).There was no difference in the number of BrdU+ cells between MCAO versus Sham + MCAO groups and IP + MCAO versus PTS+MCAO groups(P＞0.05).DOR and Bcl-2 mRNA expression levels were higher and Bax mRNA expression level was lower in IP+ MCAO group than in MCAO,Sham+ MCAO and PTS+MCAO groups (P＜0.01).There were no significant differences in DOR,Bcl-2 and Bax mRNA expressions among MCAO,Sham + MCAO and PTS + MCAO groups (P＞ 0.05).Conclusions Acute cerebral infarction can induce the proliferation of endogenous neural stem cells in hippocampus in SD rats.IPC can facilitate the proliferation of endogenous neural stem cells in hippocampus afteracute cerebral infarction,improve the symptoms of neurologic dysfunction,increase DOR and Bcl 2 mRNA expressions,and reduce Bax mRNA expression in SD rats.PTS can facilitate the proliferation of endogenous neural stem cells in hippocampus after acute cerebral infarction in SD rats,and improve the symptoms of neurologic dysfunction,but it has no influence on the expressions of DOR,Bcl-2 and Bax mRNA.

Endometrial adult/progenitor stem cells: pathogenetic theory and new antiangiogenic approach for endometriosis therapy.

The cyclical arrival of endometrial cells into the abdominal cavity through retrograde flux at menstruation represents the etiopathogenetic basis of endometriosis. The endometrium has peculiar regenerative properties linked to the presence of adult stem cells similar to mesenchymal stem cells (MSCs). Once in the abdominal cavity, these MSCs could proliferate, invade, and differentiate into endometrial cells, finally generating ectopic implants. As only differentiated endometrial cells, and not endometrial MSCs, possess steroid hormone receptors, MSCs could be responsible for the high rate of persistence/recurrence of the disease after hypoestrogenism-inducing therapies. Even angiogenesis promoted by MSCs could play an important role, as survival and proliferation of endometriotic tissue depend on the formation of new blood vessels. Inhibition of angiogenesis represents, in fact, a new, promising therapeutic approach for the disease. Further, medications directly targeting endometriosis MSCs could be effective, alone or in association with hormonal treatments, in increasing the success of medical treatment.

Pigment epithelium-derived factor enhances differentiation and mineral deposition of human mesenchymal stem cells.

Pigment epithelium-derived factor (PEDF) is a potent antiangiogenic factor found in a wide variety of tissues. Recent findings indicated that lack of PEDF leads to osteogenesis imperfecta type VI whose hallmark is a defect in mineralization. We investigated the effects of PEDF on human mesenchymal stem cells (hMSCs) and signaling pathways through which PEDF displays its activities in hMSCs. hMSCs incubated in a medium supplemented with PEDF induced expression of osteoblastic-related genes. In addition, PEDF induced alkaline phosphatase (ALP) activity in MSCs at 14 days of incubation in maintenance medium; hMSCs incubated in osteogenic medium in presence of PEDF expressed 19% more ALP activity (35.655 ± 1.827 U/mg protein, p = .041 than cells incubated in the same medium without PEDF supplementation (29.956 ± 2.100 U/µg protein). hMSCs incubated in osteogenic medium in presence of PEDF deposited 50% more mineral (2.108 ± 0.306 OD/ml per well per 1 × 10(4) cells per square centimeter, p = .017) than MSCs incubated in absence of the protein (1.398 ± 0.098 OD/ml per well per 1 × 10(4) cells per square centimeter) as determined by Alizarin Red quantitation. Reduction in PEDF expression in MSCs by siRNA led to decreased ALP activity (33.552 ± 2.009 U/ng protein of knockdown group vs. 39.269 ± 3.533 U/ng protein of scrambled siRNA group, p = .039) and significant reduction in mineral deposition (0.654 ± 0.050 OD/ml per well per 1 × 10(4) cells per square centimeter of knockdown group vs. 1.152 ± 0.132 OD/ml per well per 1 × 10(4) cells per square centimeter of wild-type group, p = .010). Decreased ALP activity and mineral deposition were restored by supplementation with exogenous PEDF protein. PEDF activated ERK and AKT signaling pathways in MSCs to induce expression of osteoblastic-related genes. These data suggest that PEDF is involved in MSCs osteoblastic differentiation.

Concise review: the yin and yang of intestinal (cancer) stem cells and their progenitors.

The intestine has developed over the last few years into a prime model system for adult stem cell research. Intestinal cells have an average lifetime of 5 days, moving within this time from the bottom of intestinal crypts to the top of villi. This rapid self-renewal capacity combined with an easy to follow (mostly) unidirectional movement of cells offers an ideal site to conduct adult stem cell research. The delineation of the active pathways in the intestinal epithelium together with the development of molecular techniques to prove stemness laid the grounds for the identification of the intestinal stem cell. In vitro systems and transgenic mouse models broaden our knowledge on the role of the stem cell niche and those cells that reestablish homeostasis after perturbation of the system. These insights expedited also research on the role of normal adult stem cells in cancer initiation and the factors influencing the maintenance of cancer stem cells.

Stem cells: general information and perspectives

We are now in the middle of stem cell war. Each country is trying to invest a large amount of funds into stem cell research. This is due to a potentiality of stem cells. Stem cells are capable of proliferating in an undifferentiated manner and are able to differentiate into a desired cell lineage under certain conditions. These abilities make stem cells an appealing source for cell replacement therapies (regenerative medicine), the study of developmental biology and drug/toxin screening. In addition to embryonic and adult stem cells, induced pluripotent stem (iPS) cells has been recently generated through reprogramming from adult tissue cells such as fibroblasts. This technique has opened up new avenues to generate patient- and disease-specific pluripotent stem cells. Human iPS cells may be useful for gaining valuable insight into the pathophysiology of disease, as well as for discovering for new prognostic biomarkers and drug screening. Moreover, the iPS cell technology may play a major role in immune-matched clinical application in the future. In this chapter, we introduce general characteristics of various stem cells, clinical application of stem cells and future perspectives.

Stem cells derived from cord blood in transplantation and regenerative medicine.

BACKGROUND: Physicians of any specialty may be the first persons to whom prospective parents turn for information about the acquisition and storage of stem cells derived from cord blood. Stem cells can potentially be used to treat many diseases, yet they are not a panacea. This article provides an overview of their current and possible future applications. METHODS: Original papers were retrieved by a selective search of the literature, and the Internet sites and advertising brochures of private stem cell banks were also examined. RESULTS: Allogeneic hematopoietic stem cells derived from umbilical cord blood (obtained from healthy donors, rather than from the patient to be treated) have been in routine use worldwide for more than ten years in the treatment of hematopoietic diseases. Experiments in cell culture and in animal models suggest that these cells might be of therapeutic use in regenerative medicine, but also show that this potential can be realized only if the cells are not cryopreserved. There is as yet no routine clinical application of autologous hematopoietic stem cells from cord blood (self-donation of blood), even though cord blood has been stored in private banks for more than ten years. CONCLUSIONS: Autologous stem cells from cord blood have poor prospects for use in regenerative medicine, because they have to be cryopreserved until use. Physicians should tell prospective parents that they have no reason to feel guilty if they choose not to store cord blood in a private bank.