Plasma miRNA profile is a biomarker associated with urothelial carcinoma in chronic hemodialysis patients.

The incidence of urothelial carcinoma (UC) is higher in patients undergoing chronic dialysis than in the general population. This study investigated plasma miRNA profiling as the ancillary diagnosis biomarker associated with UC in patients undergoing chronic hemodialysis. We successfully screened out and detected miRNA expression from plasma in eight patients undergoing dialysis through quantitative real-time PCR array analysis and identified eight candidate miRNAs. The candidate miRNAs were then validated using single quantitative RT-PCR assays from 52 plasma samples. The miRNA classifier for ancillary UC detection was developed by multiple logistic regression analyses. Moreover, we validated the classifier by testing another nine samples. Expression levels of miR-150-5p, miR-150-5p/miR-155-5p, miR-378a-3p/miR-150-5p, miR-636/miR-150-5p, miR-150-5p/miR-210-3p, and miR-19b-1-5p/miR-378a-3p were shown to be significantly different between UC and non-UC samples (P = 0.035, 0.0048, 0.016, 0.024, 0.038, and 0.048). Kaplan-Meier curve analysis also showed that low miR-19b-1-5p expression was associated with a worse prognosis (P = 0.0382). We also developed a miRNA classifier based on five miRNA expression levels to predict UC and found that the area under curve was 0.882. The classifier had a sensitivity of 80% (95% confidence interval: 0.5191% to 0.9567%) and a specificity of 83.7% (95% confidence interval: 0.6799% to 0.9381%). This classifier was tested by nine samples with 100% accuracy. The miRNA classifier offers higher sensitivity and specificity than the existing makers. Thus, this approach will improve the prospective diagnosis of UC in patients undergoing chronic hemodialysis.

microRNA expression pattern as an ancillary prognostic signature for radiotherapy.

BACKGROUND: In view of the limited knowledge of plasma biomarkers relating to cancer resistance to radiotherapy, we have set up screening, training and testing stages to investigate the microRNAs (miRNAs) expression profile in plasma to predict between the poor responsive and responsive groups after 6 months of radiotherapy. METHODS: Plasma was collected prior to and after radiotherapy, and the microRNA profiles were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) arrays. Candidate miRNAs were validated by single qRT-PCR assays from the training and testing set. The classifier for ancillary prognosis was developed by multiple logistic regression analysis to correlate the ratios of miRNAs expression levels with clinical data. RESULTS: We revealed that eight miRNAs expressions had significant changes after radiotherapy and the expression levels of miR-374a-5p, miR-342-5p and miR-519d-3p showed significant differences between the responsive and poor responsive groups in the pre-radiotherapy samples. The Kaplan-Meier curve analysis also showed that low miR-342-5p and miR-519d-3p expressions were associated with worse prognosis. Our results revealed two miRNA classifiers from the pre- and post-radiotherapy samples to predict radiotherapy response with area under curve values of 0.8923 and 0.9405. CONCLUSIONS: The expression levels of miR-374a-5p, miR-342-5p and miR-519d-3p in plasma are associated with radiotherapy responses. Two miRNA classifiers could be developed as a potential non-invasive ancillary tool for predicting patient response to radiotherapy.

PACAP38/PAC1 signaling induces bone marrow-derived cells homing to ischemic brain.

Understanding stem cell homing, which is governed by environmental signals from the surrounding niche, is important for developing effective stem cell-based repair strategies. The molecular mechanism by which the brain under ischemic stress recruits bone marrow-derived cells (BMDCs) to the vascular niche remains poorly characterized. Here we report that hypoxia-inducible factor-1α (HIF-1α) activation upregulates pituitary adenylate cyclase-activating peptide 38 (PACAP38), which in turn activates PACAP type 1 receptor (PAC1) under hypoxia in vitro and cerebral ischemia in vivo. BMDCs homing to endothelial cells in the ischemic brain are mediated by HIF-1α activation of the PACAP38-PAC1 signaling cascade followed by upregulation of cellular prion protein and α6-integrin to enhance the ability of BMDCs to bind laminin in the vascular niche. Exogenous PACAP38 confers a similar effect in facilitating BMDCs homing into the ischemic brain, resulting in reduction of ischemic brain injury. These findings suggest a novel HIF-1α-activated PACAP38-PAC1 signaling process in initiating BMDCs homing into the ischemic brain for reducing brain injury and enhancing functional recovery after ischemic stroke.

Trans-kingdom rescue of Gln-tRNAGln synthesis in yeast cytoplasm and mitochondria.

Aminoacylation of transfer RNA(Gln) (tRNA(Gln)) is performed by distinct mechanisms in different kingdoms and represents the most diverged route of aminoacyl-tRNA synthesis found in nature. In Saccharomyces cerevisiae, cytosolic Gln-tRNA(Gln) is generated by direct glutaminylation of tRNA(Gln) by glutaminyl-tRNA synthetase (GlnRS), whereas mitochondrial Gln-tRNA(Gln) is formed by an indirect pathway involving charging by a non-discriminating glutamyl-tRNA synthetase and the subsequent transamidation by a specific Glu-tRNA(Gln) amidotransferase. Previous studies showed that fusion of a yeast non-specific tRNA-binding cofactor, Arc1p, to Escherichia coli GlnRS enables the bacterial enzyme to substitute for its yeast homologue in vivo. We report herein that the same fusion enzyme, upon being imported into mitochondria, substituted the indirect pathway for Gln-tRNA(Gln) synthesis as well, despite significant differences in the identity determinants of E. coli and yeast cytosolic and mitochondrial tRNA(Gln) isoacceptors. Fusion of Arc1p to the bacterial enzyme significantly enhanced its aminoacylation activity towards yeast tRNA(Gln) isoacceptors in vitro. Our study provides a mechanism by which trans-kingdom rescue of distinct pathways of Gln-tRNA(Gln) synthesis can be conferred by a single enzyme.

Neocartilage formation from mesenchymal stem cells grown in type II collagen-hyaluronan composite scaffolds.

Three-dimensional (3D) collagen type II-hyaluronan (HA) composite scaffolds (CII-HA) which mimics the extracellular environment of natural cartilage were fabricated in this study. Rheological measurements demonstrated that the incorporation of HA increased the compression modulus of the scaffolds. An initial in vitro evaluation showed that scaffolds seeded with porcine chondrocytes formed cartilaginous-like tissue after 8 weeks, and HA functioned to promote the growth of chondrocytes into scaffolds. Placenta-derived multipotent cells (PDMC) and gingival fibroblasts (GF) were seeded on tissue culture polystyrene (TCPS), CII-HA films, and small intestinal submucosa (SIS) sheets for comparing their chondrogenesis differentiation potentials with those of adipose-derived adult stem cells (ADAS) and bone marrow-derived mesenchymal stem cells (BMSC). Among different cells, PDMC showed the greatest chondrogenic differentiation potential on both CII-HA films and SIS sheets upon TGF-ß3 induction, followed by GF. This was evidenced by the up-regulation of chondrogenic genes (Sox9, aggrecan, and collagen type II), which was not observed for cells grown on TCPS. This finding suggested the essential role of substrate materials in the chondrogenic differentiation of PDMC and GF. Neocartilage formation was more obvious in both PDMC and GF cells plated on CII-HA composite scaffolds vs. 8-layer SIS at 28 days in vitro. Finally, implantation of PDMC/CII-HA constructs into NOD-SCID mice confirmed the formation of tissue-engineered cartilage in vivo.

Role of HIF-1α-activated Epac1 on HSC-mediated neuroplasticity in stroke model.

Exchange protein activated by cAMP-1 (Epac1) plays an important role in cell proliferation, cell survival and neuronal signaling, and activation of Epac1 in endothelial progenitor cells increases their homing to ischemic muscles and promotes neovascularization in a model of hind limb ischemia. Moreover, upregulation of Epac1 occurs during organ development and in diseases such as myocardial hypertrophy, diabetes, and Alzheimer's disease. We report here that hypoxia upregulated Epac1 through HIF-1α induction in the CD34-immunosorted human umbilical cord blood hematopoietic stem cells (hUCB(34)). Importantly, implantation of hUCB(34) subjected to hypoxia-preconditioning (HP-hUCB(34)) improved stroke outcome, more than did implantation of untreated hUCB(34), in rodents subjected to cerebral ischemia, and this required Epac1-to-matrix metalloprotease (MMP) signaling. This improved therapeutic efficacy correlated with better engraftment and differentiation of these cells in the ischemic host brain. In addition, more than did implantation of untreated HP-hUCB(34), implantation of HP-hUCB(34) improved cerebral blood flow into the ischemic brain via induction of angiogenesis, facilitated proliferation/recruitment of endogenous neural progenitor cells in the ischemic brain, and promoted neurite outgrowth following cerebral ischemia. Consistent with our proposed role of Epac1-to-MMP signaling in hypoxia-preconditioning, the above mentioned effects of implanting HP-hUCB(34) could be abolished by pharmacological inhibition and genetic disruption/deletion of Epac1 or MMPs. We have discovered a HIF-1α-to-Epac1-to-MMP signaling pathway that is required for the improved therapeutic efficacy resulting from hypoxia preconditioning of hUCB(34) in vitro prior to their implantation into the host brain in vivo.

A tryptophan-rich peptide acts as a transcription activation domain.

BACKGROUND: Eukaryotic transcription activators normally consist of a sequence-specific DNA-binding domain (DBD) and a transcription activation domain (AD). While many sequence patterns and motifs have been defined for DBDs, ADs do not share easily recognizable motifs or structures. RESULTS: We report herein that the N-terminal domain of yeast valyl-tRNA synthetase can function as an AD when fused to a DNA-binding protein, LexA, and turn on reporter genes with distinct LexA-responsive promoters. The transcriptional activity was mainly attributed to a five-residue peptide, WYDWW, near the C-terminus of the N domain. Remarkably, the pentapeptide per se retained much of the transcriptional activity. Mutations which substituted tryptophan residues for both of the non-tryptophan residues in the pentapeptide (resulting in W5) significantly enhanced its activity (~1.8-fold), while mutations which substituted aromatic residues with alanine residues severely impaired its activity. Accordingly, a much more active peptide, pentatryptophan (W7), was produced, which elicited ~3-fold higher activity than that of the native pentapeptide and the N domain. Further study indicated that W7 mediates transcription activation through interacting with the general transcription factor, TFIIB. CONCLUSIONS: Since W7 shares no sequence homology or features with any known transcription activators, it may represent a novel class of AD.

A single sequence context cannot satisfy all non-AUG initiator codons in yeast.

BACKGROUND: Previous studies in Saccharomyces cerevisiae showed that ALA1 (encoding alanyl-tRNA synthetase) and GRS1 (encoding glycyl-tRNA synthetase) respectively use ACG and TTG as their alternative translation initiator codons. To explore if any other non-ATG triplets can act as initiator codons in yeast, ALA1 was used as a reporter for screening. RESULTS: We show herein that except for AAG and AGG, all triplets that differ from ATG by a single nucleotide were able to serve as initiator codons in ALA1. Among these initiator codons, TTG, CTG, ACG, and ATT had ~50% initiating activities relative to that of ATG, while GTG, ATA, and ATC had ~20% initiating activities relative to that of ATG. Unexpectedly, these non-AUG initiator codons exhibited different preferences toward various sequence contexts. In particular, GTG was one of the most efficient non-ATG initiator codons, while ATA was essentially inactive in the context of GRS1. CONCLUSION: This finding indicates that a sequence context that is favorable for a given non-ATG initiator codon might not be as favorable for another.

miR-524-5p reduces the progression of the BRAF inhibitor-resistant melanoma.

BRAF inhibitors were approved for the treatment of BRAF-mutant melanoma. However, most patients acquire the resistance to BRAF inhibitors after several months of treatment. miR-524-5p is considered as a tumor suppressor in many cancers, including melanoma. In this study, we investigated the biological functions of miR-524-5p in melanoma with acquired resistance to BRAF inhibitor and evaluated the endogenous miR-524-5p expression as a biomarker for melanoma. The results showed that the expression of miR-524-5p was 0.481-fold lower in melanoma tissues (n = 117) than in nevus tissues (n = 40). Overexpression of miR-524-5p significantly reduced proliferative, anchorage-independent growth, migratory and invasive abilities of BRAF inhibitor-resistant melanoma cells. Moreover, the introduction of miR-524-5p led to a reduced development of BRAF inhibitor-resistant melanoma in vivo. Remarkably, the MAPK/ERK signaling pathway was decreased after treatment with miR-524-5p. Furthermore, next-generation sequencing analysis implied that the complement system, leukocyte extravasation, liver X receptor/retinoid-X-receptor activation, and cAMP-mediated signaling may be related to miR-524-5p-induced pathways in the resistant cells. The miR-524-5p level was higher on average in complete response and long-term partial response patients than in progressive disease and short-term partial response patients treated with BRAF inhibitors. Our results proposed that miR-524-5p could be considered as a target for treatment BRAF inhibitor-resistant melanoma and a prognostic marker in the response of patients to BRAF inhibitors for melanoma.

miR-596 Modulates Melanoma Growth by Regulating Cell Survival and Death.

Tumors grow because cancer cells lack the ability to balance cell survival and death signaling pathways. miR-596, a microRNA located at the 8p23.3 locus, has been shown by the TCGA-Assembler to be deleted in a significant number of melanoma samples. Here, we also validated the low levels of miR-596 in melanoma compared to tissue nevi, and Kaplan-Meier curve analysis revealed that low miR-596 expression was associated with worse overall survival. Moreover, we showed that miR-596 overexpression effectively inhibited MAPK/ERK signaling, cell proliferation, migration, and invasion and increased the cell apoptosis of melanoma cells. In addition, we found that miR-596 directly targets MEK1 and two apoptotic proteins, MCL1, and BCL2L1, in melanoma cells. Our findings indicated that miR-596 is an important miRNA that both negatively regulates the MAPK/ERK signaling pathway by targeting MEK1 and modulates the apoptosis pathway by targeting MCL1 and BCL2L1, suggesting that miR-596 could be a therapeutic candidate for treating melanoma, and a prognostic factor for melanoma patients.

Increase of Meningitis Risk in Stroke Patients in Taiwan.

BACKGROUND AND PURPOSE: The blood-brain barrier (BBB) not only provides a physical obstruction but also recruits and activates neutrophils in cases of infection. Hemorrhagic or ischemic stroke reportedly induces the disruption of the BBB. However, few studies have reported a correlation between the incidence of meningitis in patients with a history of stroke. This study tested the hypothesis that patients with a history of stroke may be more vulnerable to meningitis. METHODS: Stroke and age-matched comparison (n = 29,436 and 87,951, respectively) cohorts were recruited from the Taiwan National Health Insurance database (2000-2011). Correlations between the two cohorts were evaluated by Cox proportional hazard regression model, Kaplan-Meier curve, and log-rank tests. RESULTS: The incidence of meningitis was higher in the stroke cohort compared to that in the comparison cohort [hazard ratio (HR), 2.89; 95% confidence interval (CI), 2.23-3.74, p < 0.001]. After adjusting for age, sex, and comorbidities, the estimated HR in the stroke cohort was 2.55-fold higher than that in the comparison cohort (CI, 1.94-3.37; p < 0.001). Notably, patients who had experienced hemorrhagic stroke had a higher incidence rate of meningitis than those with a history of ischemic stroke, except for patients older than 75 years (incidence rates in hemorrhagic/ischemic stroke patients, 3.14/1.48 in patients younger than 45 years, 1.52/0.41 in 45- to 64-year group, 1.15/0.90 in 65- to 74-year group, 0.74/0.93 in patients older than 75 years). Moreover, stroke patients who had undergone head surgery had the highest meningitis risk (adjusted HR, 8.66; 95% CI, 5.55-13.5; p < 0.001) followed by stroke patients who had not undergone head surgery (adjusted HR, 2.11; 95% CI, 1.57-2.82; p < 0.001). CONCLUSION: Our results indicated that stroke patients have higher risks of meningitis. Compromised BBB integrity in stroke patients may lead to increased vulnerability to infectious pathogens. In summary, our study provided new evidence of the clinical relationship between stroke and meningitis, and our findings suggest the need for precautions to prevent meningitis in stroke patients.

Potential role of CBX7 in regulating pluripotency of adult human pluripotent-like olfactory stem cells in stroke model.

The adult olfactory mucosa, a highly regenerative tissue with unique life-long neurogenesis ability, is thought to harbor a naïve yet tightly controlled stem cell population. It will provide unique benefits in various stem cell-based therapies, such as stroke treatment. Here, we identified a subpopulation of adult pluripotent-like olfactory stem cells (APOSCs), which were modulated by an epigenetic repressor of CBX7. APOSCs form a floating sphere, express pluripotency markers Nanog, Oct-4, Sox-2, and SSEA-4 and show alkaline phosphatase activity. In addition, APOSCs display self-renewal and a pluripotent potential to differentiate into all three germ layers. Moreover, APOSCs coexpress pluripotency markers with CBX7. Within their natural niche, APOSCs from CBX7+/+ mice responded promptly to either spontaneous or injury-induced tissue regeneration. However, APOSCs from CBX7-/- mice manifested an impaired self-renewal and differentiation potential. Similarly, in vitro-cultivated CBX7-/- APOSCs underwent premature senescence, whereas CBX7+/+ APOSCs still actively divided, indicating that CBX7 is required for the self-renewal of APOSCs. Intracerebral implantation of APOSCs improved the stroke-mediated neurological dysfunction in rodents. These findings indicate that CBX7 plays a critical role in the regenerative properties of APOSCs and indicate the safety and feasibility of implantation of autologous APOSCs in stroke treatment.

The properties of gelatin-poly (gamma-glutamic acid) hydrogels as biological glues.

The influence of the molecular weight and the type of gelatin (A or B), as well as the molecular weight of poly (gamma-glutamic acid) (gamma-PGA), on the properties of gelatin/gamma-PGA mixed bioadhesives were studied. The gelation of the system was enhanced by a crosslinker, 1-(3-dimethylaminopropyl)-3-(ethylcarbodiimide) hydrochloride (EDC). The gelation time of the bioadhesives was analyzed using rheological measurements. The results indicated that the type of gelatin was a critical factor in determining the gelation time of the biological glues. The mixed glues had greater bonding strength and smaller gelation times as the molecular weight of gamma-PGA or gelatin increased. The swelling ratio decreased and the denaturation temperature increased upon raising the EDC concentration, indicating a greater degree of crosslinking at higher EDC concentrations. The mixed glues crosslinked with various concentrations of EDC (1.7-2.5%) showed no cytotoxicity to fibroblasts. In addition, no significant inflammatory response was observed in the rat subcutaneous implantation. The bioadhesives based on gelatin/gamma-PGA remained at the site for 7 days while the fibrin glue had almost completely degraded. By choosing the appropriate gelatin type and higher molecular weight gamma-PGA in the mixtures, the gelatin/gamma-PGA biological glues could serve as soft tissue adhesives. Rheological characterization was essential in the evaluation of biological glues.

IGF1R+ Dental Pulp Stem Cells Enhanced Neuroplasticity in Hypoxia-Ischemia Model.

Until now, the surface markers of multipotent mesenchymal stem cells (MSCs) had not been fully identified. Here, we found that the IGF1 receptor (IGF1R), regarded as a pluripotent marker of embryonic stem cells (ESCs), was also expressed in human dental pulp derived-mesenchymal stem cells (hDSCs), which displayed a potential for both self-renewal and multipotency. hDSC-secreted IGF1 interacted with IGF1R through an autocrine signaling pathway to maintain this self-renewal and proliferation potential. Stereotaxic implantation of immunosorted IGF1R+ hDSCs in rats with neonatal hypoxia-ischemia (NHI) promoted neuroplasticity, improving the neurological outcome by increasing expression of the anti-apoptotic protein Bcl-2, which enhanced both neurogenesis and angiogenesis. In addition, treatment with IGF1R+ hDSCs significantly modulated neurite regeneration and anti-inflammation in vivo in NHI rats and in vitro in primary cortical cultures under oxygen/glucose deprivation. Autocrine regulatory expression of IGF1R contributed to maintaining the self-renewal capacity of hDSCs. Furthermore, implantation of IGF1R+ hDSCs increased neuroplasticity with neurite regeneration and immunomodulation in and the NHI rat model.

A Crucial Role of CXCL14 for Promoting Regulatory T Cells Activation in Stroke.

Inflammatory processes have a detrimental role in the pathophysiology of ischemic stroke. However, little is known about the endogenous anti-inflammatory mechanisms in ischemic brain. Here, we identify CXCL14 as a critical mediator of these mechanisms. CXCL14 levels were upregulated in the ischemic brains of humans and rodents. Moreover, hypoxia inducible factor-1α (HIF-1α) drives hypoxia- or cerebral ischemia (CI)-dependent CXCL14 expression via directly binding to the CXCL14 promoter. Depletion of CXCL14 inhibited the accumulation of immature dendritic cells (iDC) or regulatory T cells (Treg) and increased the infarct volume, whereas the supplementation of CXCL14 had the opposite effects. CXCL14 promoted the adhesion, migration, and homing of circulating CD11c+ iDC to the ischemic tissue via the upregulation of the cellular prion protein (PrPC), PECAM-1, and MMPs. The accumulation of Treg in ischemic areas of the brain was mediated through a cooperative effect of CXCL14 and iDC-secreted IL-2-induced Treg differentiation. Interestingly, CXCL14 largely promoted IL-2-induced Treg differentiation. These findings indicate that CXCL14 is a critical immunomodulator involved in the stroke-induced inflammatory reaction. Passive CXCL14 supplementation provides a tractable path for clinical translation in the improvement of stroke-induced neuroinflammation.

CCM111, the water extract of Antrodia cinnamomea, regulates immune-related activity through STAT3 and NF-κB pathways.

Antrodia cinnamomea (AC) exhibits many bioactivities, including anti-inflammatory, anti-cancer, and hepatoprotection activities. Many researchers have studied the functions of the components or fractions of AC, but the functions of the original extractions of AC have not been studied. In addition, the detailed relationship between AC and immune-related signaling pathways is unclear. In this study, we screened the effects of CCM111, which is the extract of AC, on seven immune-related signaling pathways and further investigated whether CCM111 can influence inflammation. Interestingly, our results showed that CCM111 significantly inhibited the IL-6-stimulated STAT3 pathway and the LPS-stimulated NF-κB pathway in macrophages. CCM111 also decreased the phosphorylation of STAT3, Tyk2 and the nuclear translocation of p65. Moreover, CCM111 and F4, a fraction of CCM111, down-regulated nitric oxide (NO) production, the protein levels of iNOS and COX-2, and inflammatory cytokines in macrophage cells. Therefore, our study suggested that CCM111 has the potential to be developed as an effective anti-inflammatory agent.

The effect of ultrasound stimulation versus bioreactors on neocartilage formation in tissue engineering scaffolds seeded with human chondrocytes in vitro.

Pulsed ultrasound (1 MHz, 67 mW/cm(2) Ispta, and 10 min/day) promoted cell proliferation and matrix deposition in low-density 2D ( approximately 6 x 10(3)cells/cm(2)) as well as 3D ( approximately 4 x 10(6)cells/cm(3)) chondrocyte cultures. The beneficial effect of ultrasound on neocartilage formation only last 28 days, shorter than that of bioreactors.

Electrospun Polyacrylonitrile-Based Nanofibers Maintain Embryonic Stem Cell Stemness via TGF-Beta Signaling.

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are capable of self-renewal and differentiation into any cell type, thus making them the focus of many clinical application studies. Culturing ESCs on mouse embryonic fibroblast-derived and cell-based feeder layers to maintain pluripotency is a standard laboratory procedure. However, xenogeneic contamination and the large amount of time required for feeder cell preparation are two challenges that encourage the use of a murine-based feeder layer. A novel biomaterial is required to replace the current cell-based feeder system. Toward this goal, we applied a combination of biocompatible polyacrylonitrile (PAN) and electrospinning technology to establish a non-cell-based feeder layer. According to results from stem cell marker staining, scanning electron microscopy, and embryoid body formation tests, optimal ESC stemness and pluripotency were noted in three electrospun groups (2, 4, and 8 minutes), with the longer electrospinning times producing higher feeder-layer densities. KEGG pathway microarray results identified TGF-beta signaling as one of the major deregulatory pathways on electrospun-based feeder layers. Western blot data indicate significant increases in TGF-beta receptor II, phosphorylated Smad3, and Nanog protein levels in the 4- and 8-minute electrospun-based feeder layer groups compared to the non-feeder layer group. Combined, the data suggest that electrospun-based feeder layers are good candidates for maintaining ESC and iPSC pluripotency in clinical applications.

Role of IGF1R(+) MSCs in modulating neuroplasticity via CXCR4 cross-interaction.

To guide the use of human mesenchymal stem cells (MSCs) toward clinical applications, identifying pluripotent-like-markers for selecting MSCs that retain potent self-renewal-ability should be addressed. Here, an insulin-like growth factor 1 receptor (IGF1R)-expressing sub-population in human dental pulp MSCs (hDSCs), displayed multipotent properties. IGF1R expression could be maintained in hDSCs when they were cultured in 2% human cord blood serum (hUCS) in contrast to that in 10% fetal calf serum (FCS). Cytokine array showed that hUCS contained higher amount of several growth factors compared to FCS, including IGF-1 and platelet-derived growth factor (PDGF-BB). These cytokines modulates the signaling events in the hDSCs and potentially enhances engraftment upon transplantation. Specifically, a bidirectional cross-talk between IGF1R/IGF1 and CXCR4/SDF-1α signaling pathways in hDSCs, as revealed by interaction of the two receptors and synergistic activation of both signaling pathways. In rat stroke model, animals receiving IGF1R(+) hDSCs transplantation, interaction between IGF1R and CXCR4 was demonstrated to promote neuroplasticity, therefore improving neurological function through increasing glucose metabolic activity, enhancing angiogenesis and anti-inflammatiory effects. Therefore, PDGF in hUCS-culture system contributed to the maintenance of the expression of IGF1R in hDSCs. Furthermore, implantation of IGF1R(+) hDSCs exerted enhanced neuroplasticity via integrating inputs from both CXCR4 and IGF1R signaling pathways.

Multitheragnostic Multi-GNRs Crystal-Seeded Magnetic Nanoseaurchin for Enhanced In Vivo Mesenchymal-Stem-Cell Homing, Multimodal Imaging, and Stroke Therapy.

A multifunctional nanoseaurchin probe in which mesoporous silica nanobeads with iron oxide nanoparticles embedded and multi-gold nanorods crystal-seeded are fabricated and labeled with umbilical cord mesenchymal stem cells through endocytosis. This nanoplatform enables efficient magnetic remote-controlled guiding for stem cell homing, and provides dual modalities of photoacoustic imaging and magnetic resonance imaging for in situ tracking and long-term monitoring to achieve therapeutic efficacy.