Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine

Guangzhou, China

Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine

Guangzhou, China

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Li X.,City University of Hong Kong | Li X.,Hong Kong Polytechnic University | Li X.,University of Chinese Academy of Sciences | Yu K.,Hong Kong Polytechnic University | And 22 more authors.
Cell Research | Year: 2014

Patients with damage to the medial temporal lobe show deficits in forming new declarative memories but can still recall older memories, suggesting that the medial temporal lobe is necessary for encoding memories in the neocortex. Here, we found that cortical projection neurons in the perirhinal and entorhinal cortices were mostly immunopositive for cholecystokinin (CCK). Local infusion of CCK in the auditory cortex of anesthetized rats induced plastic changes that enabled cortical neurons to potentiate their responses or to start responding to an auditory stimulus that was paired with a tone that robustly triggered action potentials. CCK infusion also enabled auditory neurons to start responding to a light stimulus that was paired with a noise burst. In vivo intracellular recordings in the auditory cortex showed that synaptic strength was potentiated after two pairings of presynaptic and postsynaptic activity in the presence of CCK. Infusion of a CCKB antagonist in the auditory cortex prevented the formation of a visuo-auditory association in awake rats. Finally, activation of the entorhinal cortex potentiated neuronal responses in the auditory cortex, which was suppressed by infusion of a CCKB antagonist. Together, these findings suggest that the medial temporal lobe influences neocortical plasticity via CCK-positive cortical projection neurons in the entorhinal cortex. © 2014 IBCB, SIBS, CAS.


Du J.,University of Wisconsin - Madison | Wang J.,University of Wisconsin - Madison | Wang J.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine | Kong G.,University of Wisconsin - Madison | And 6 more authors.
Stem Cells | Year: 2012

Hematopoietic stem cell (HSC) function is tightly regulated by cytokine signaling. Although phospho-flow cytometry allows us to study signaling in defined populations of cells, there has been tremendous hurdle to carry out this study in rare HSCs due to unrecoverable critical HSC markers, low HSC number, and poor cell recovery rate. Here, we overcame these difficulties and developed a "HSC phospho-flow" method to analyze cytokine signaling in murine HSCs at the single-cell level and compare HSC signaling profile to that of multipotent progenitors (MPPs), a cell type immediately downstream of HSCs, and commonly used Lin- cKit+ cells (LK cells, enriched for myeloid progenitors). We chose to study signaling evoked from three representative cytokines, stem cell factor (SCF) and thrombopoietin (TPO) that are essential for HSC function and granulocyte macrophage-colony-stimulating factor (GM-CSF) that is dispensable for HSCs. HSCs display a distinct TPO and GM-CSF signaling signature from MPPs and LK cells, which highly correlates with receptor surface expression. In contrast, although majority of LK cells express lower levels of cKit than HSCs and MPPs, SCF-evoked ERK1/2 activation in LK cells shows a significantly increased magnitude for a prolonged period. These results suggest that specific cellular context plays a more important role than receptor surface expression in SCF signaling. Our study of HSC signaling at the homeostasis stage paves the way to investigate signaling changes in HSCs under conditions of stress, aging, and hematopoietic diseases. © AlphaMed Press.


Yang D.,Sun Yat Sen University | Yang D.,Chinese Academy of Sciences | Zhang X.,Sun Yat Sen University | Dong Y.,Chinese Academy of Sciences | And 13 more authors.
Cell Cycle | Year: 2015

Hoxa5 is preferentially expressed in haematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs), and is more highly expressed in expanding HSCs. To date, little is known regarding the role of Hoxa5 in HSCs and downstream progenitor cells in vivo. In this study, we show that increased expression of Hoxa5 in haematopoietic stem cells leads to aberrant erythropoiesis in vivo. Hoxa5 differentially modi fies the cell cycle of HSCs and lineage committed progenitor cells, depending on the cellular context. Hoxa5 drives HSCs, but not MPPs, through the cell cycle and arrests erythroid progenitor cells in G0 phase. Although the HSC pool shrinks after overexpression of Hoxa5, HSCs sustain the abilities of self-renewal and multipotency. In vivo, Hoxa5 has two effects on erythropoiesis: it causes a predominance of mature erythroid lineage cells and the partial apoptosis of erythroid progenitors. RNA-seq indicates that multiple biological processes, including erythrocyte homeostasis, cell metabolism, and apoptosis, are modified by Hoxa5. The results of this study indicate that Hoxa5 is a key regulator of the HSC cell cycle, and the inappropriate expression of Hoxa5 in lineagecommitted progenitor cells leads to aberrant erythropoiesis. © 2015 Taylor & Francis Group, LLC.


Luo B.,Anhui Medical University | Hu L.,CAS Guangzhou Institute of Biomedicine and Health | Hu L.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine | Liu C.,CAS Guangzhou Institute of Biomedicine and Health | And 5 more authors.
Amino Acids | Year: 2015

Glycine receptors (GlyRs) permeable to chloride only mediate tonic inhibition in the cerebral cortex where glycinergic projection is completely absent. The functional modulation of GlyRs was largely studied in subcortical brain regions with glycinergic transmissions, but the function of cortical GlyRs was rarely addressed. Serotonin could broadly modulate many ion channels through activating 5-HT2 receptor, but whether cortical GlyRs are subjected to serotonergic modulation remains unexplored. The present study adopted patch clamp recordings to examine functional regulation of strychnine-sensitive GlyRs currents in cultured cortical neurons by DOI (2,5-Dimethoxy-4-iodoamphetamine), a 5-HT2A/C receptor agonist. DOI caused a concentration-dependent reduction of GlyR currents with unchanged reversal potential. This reduction was blocked by the selective receptor antagonists (ritanserin and risperidone) and G protein inhibitor (GDP-β-s) demonstrated that the reducing effect of DOI on GlyR current required the activation of 5-HT2A/C receptors. Strychnine-sensitive tonic currents revealed the inhibitory tone mediated by nonsynaptic GlyRs, and DOI similarly reduced the tonic inhibition. The impaired microtube-dependent trafficking or clustering of GlyRs was thought to be involved in that nocodazole as a microtube depolymerizing drug largely blocked the inhibition mediated by 5-HT2A/C receptors. Our results suggested that activation of 5-HT2A/C receptors might suppress cortical tonic inhibition mediated by GlyRs, and the findings would provide important insight into serotonergic modulation of tonic inhibition mediated by GlyRs, and possibly facilitate to develop the therapeutic treatment of neurological diseases such as tinnitus through regulating cortical GlyRs. © 2015 Springer-Verlag Wien


Samokhvalov I.M.,Chinese Academy of Sciences | Samokhvalov I.M.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
Cellular and Molecular Life Sciences | Year: 2014

Two different models describe the development of definitive hematopoiesis and hematopoietic stem cells (HSCs). In one of these, the visceral yolk sac serves as a starting point of relatively lengthy developmental process culminating in the fetal liver hematopoiesis. In another, the origin of adult hematopoiesis is split between the yolk sac and the dorsal aorta, which has a peculiar capacity to generate definitive HSCs. Despite a large amount of experimental data consistent with the latter view, it becomes increasingly unsustainable in the light of recent cell tracing studies. Moreover, analysis of the published studies supporting the aorta-centered version uncovers significant caveats in standard experimental approach and argumentation. As a result, the theory cannot offer feasible cellular mechanisms of the HSC emergence. This review summarizes key efforts to discern the developmental pathway of the adult-type HSCs and attempts to put forward a hypothesis on the inflammatory mechanisms of hematopoietic ontogenesis. © 2013 Springer Basel.


Luo B.,Anhui Medical University | Hu L.,CAS Guangzhou Institute of Biomedicine and Health | Hu L.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine | Liu C.,CAS Guangzhou Institute of Biomedicine and Health | And 5 more authors.
Amino Acids | Year: 2016

Glycine receptors (GlyRs) permeable to chloride only mediate tonic inhibition in the cerebral cortex where glycinergic projection is completely absent. The functional modulation of GlyRs was largely studied in subcortical brain regions with glycinergic transmissions, but the function of cortical GlyRs was rarely addressed. Serotonin could broadly modulate many ion channels through activating 5-HT2 receptor, but whether cortical GlyRs are subjected to serotonergic modulation remains unexplored. The present study adopted patch clamp recordings to examine functional regulation of strychnine-sensitive GlyRs currents in cultured cortical neurons by DOI (2,5-Dimethoxy-4-iodoamphetamine), a 5-HT2A/C receptor agonist. DOI caused a concentration-dependent reduction of GlyR currents with unchanged reversal potential. This reduction was blocked by the selective receptor antagonists (ritanserin and risperidone) and G protein inhibitor (GDP-β-s) demonstrated that the reducing effect of DOI on GlyR current required the activation of 5-HT2A/C receptors. Strychnine-sensitive tonic currents revealed the inhibitory tone mediated by nonsynaptic GlyRs, and DOI similarly reduced the tonic inhibition. The impaired microtube-dependent trafficking or clustering of GlyRs was thought to be involved in that nocodazole as a microtube depolymerizing drug largely blocked the inhibition mediated by 5-HT2A/C receptors. Our results suggested that activation of 5-HT2A/C receptors might suppress cortical tonic inhibition mediated by GlyRs, and the findings would provide important insight into serotonergic modulation of tonic inhibition mediated by GlyRs, and possibly facilitate to develop the therapeutic treatment of neurological diseases such as tinnitus through regulating cortical GlyRs. © 2015 Springer-Verlag Wien.


Guo X.,CAS Guangzhou Institute of Biomedicine and Health | Guo X.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine | Zhang T.,Guangzhou University | Hu Z.,CAS Guangzhou Institute of Biomedicine and Health | And 15 more authors.
Development (Cambridge) | Year: 2014

For the emerging amphibian genetic model Xenopus tropicalis targeted gene disruption is dependent on zinc-finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs), which require either complex design and selection or laborious construction. Thus, easy and efficient genome editing tools are still highly desirable for this species. Here, we report that RNA-guided Cas9 nuclease resulted in precise targeted gene disruption in all ten X. tropicalis genes that we analyzed, with efficiencies above 45% and readily up to 100%. Systematic point mutation analyses in two loci revealed that perfect matches between the spacer and the protospacer sequences proximal to the protospacer adjacent motif (PAM) were essential for Cas9 to cleave the target sites in the X. tropicalis genome. Further study showed that the Cas9 system could serve as an efficient tool for multiplexed genome engineering in Xenopus embryos. Analysis of the disruption of two genes, ptf1a/p48 and tyrosinase, indicated that Cas9-mediated gene targeting can facilitate direct phenotypic assessment in X. tropicalis embryos. Finally, five founder frogs from targeting of either elastase-T1, elastase-T2 or tyrosinase showed highly efficient transmission of targeted mutations into F1 embryos. Together, our data demonstrate that the Cas9 system is an easy, efficient and reliable tool for multiplex genome editing in X. tropicalis. © 2014.


Chen J.,CAS Guangzhou Institute of Biomedicine and Health | Chen J.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine | Pei D.,CAS Guangzhou Institute of Biomedicine and Health | Pei D.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
IUBMB Life | Year: 2016

Cells all share essentially the same genome, which is shaped by the developmental program to bring about various outcomes. It is well known that epigenetic regulation is a key process in determining the different cell functional output from the genetic information. Somatic reprogramming is a dramatic demonstration of this effect, and has opened the gate to the investigation of cell fate determination as cells reverse the developmental program. These studies have revealed which epigenetic marks set during normal development are important for cell specification. Here, we review the epigenetic landmarks that cells pass through during somatic reprogramming, and give an overview to the many remaining unclear epigenetic regulatory events that occurs during reprogramming. © 2016 IUBMB Life, 68(11):854–857, 2016. © 2016 International Union of Biochemistry and Molecular Biology


Hu L.,Chinese Academy of Sciences | Hu L.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine | Liu C.,Chinese Academy of Sciences | Liu C.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine | And 8 more authors.
Neuroscience Letters | Year: 2016

The abundant forebrain serotonergic projections are believed to modulate the activities of cortical neurons. 5-HT2 receptor among multiple subtypes of serotonin receptors contributes to the modulation of excitability, synaptic transmissions and plasticity. In the present study, whole-cell patch-clamp recording was adopted to examine whether activation of 5-HT2A/2C receptors would have any impact on the excitability of cultured cortical neurons. We found that 2,5-Dimethoxy-4-iodoamphetamine (DOI), a selective 5-HT2A/2C receptor agonist, rapidly and reversibly depressed spontaneous action potentials mimicking the effect of serotonin. The decreased excitability was also observed for current-evoked firing. Additionally DOI increased neuronal input resistance. Hyperpolarization-activated cyclic nucleotide-gated cationic channels (HCN) did not account for the inhibition of spontaneous firing. The synaptic contribution was ruled out in that DOI augmented excitation and attenuated inhibition to actually favor an increase in the excitability. Our findings revealed that activation of 5-HT2A/2C receptors reduces neuronal excitability, which would deepen our understanding of serotonergic modulation of cortical activities. © 2016 Elsevier Ireland Ltd


Zhang T.,Chinese Academy of Sciences | Zhang T.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine | Zhang T.,University of Chinese Academy of Sciences | Guo X.,Chinese Academy of Sciences | And 3 more authors.
PLoS ONE | Year: 2013

How cells integrate multiple patterning signals to achieve early endoderm regionalization remains largely unknown. Between gastrulation and neurulation, retinoic acid (RA) signaling is required, while Wnt/β-catenin signaling has to be repressed for the specification of the pancreas, oesophagus, stomach, and duodenum primordia in Xenopus embryos. In attempt to screen for RA regulated genes in Xenopus endoderm, we identified a direct RA target gene, N-myc downstream regulated gene 1a (ndrg1a) that showed expression early in the archenteron roof endoderm and late in the developing pancreas, oesophagus, stomach, and duodenum. Both antisense morpholino oligonucleotide mediated knockdown of ndrg1a in Xenopus laevis and the transcription activator-like effector nucleases (TALEN) mediated disruption of ndrg1 in Xenopus tropicalis demonstrate that like RA signaling, Ndrg1a is specifically required for the specification of Xenopus pancreas, oesophagus, stomach, and duodenum primordia. Immunofluorescence data suggest that RA-activated Ndrg1a suppresses Wnt/β-catenin signaling in Xenopus archenteron roof endoderm cells. Blocking Wnt/β-catenin signaling rescued Ndrg1a knockdown phenotype. Furthermore, overexpression of the putative Wnt/β-catenin target gene Atf3 phenocopied knockdown of Ndrg1a or inhibition of RA signaling, while Atf3 knockdown can rescue Ndrg1a knockdown phenotype. Lastly, the pancreas/stomach/duodenum transcription factor Pdx1 was able to rescue Atf3 overexpression or Ndrg1a knockdown phenotype. Together, we conclude that RA activated Ndrg1a represses Wnt/β-catenin signaling to allow the specification of pancreas, oesophagus, stomach, and duodenum progenitor cells in Xenopus embryos. © 2013 Zhang et al.

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