Rbm46 inhibits reactive oxygen species in mouse embryonic stem cells through modulating BNIP3-mediated mitophagy.

Embryonic stem cells (ESCs) exhibit a metabolic preference for glycolysis over oxidative phosphorylation to meet their substantial adenosine triphosphate (ATP) demands during self-renewal. This metabolic choice inherently maintains low mitochondrial activity and minimal reactive oxygen species (ROS) generation. Nonetheless, the intricate molecular mechanisms governing the restraint of ROS production and the mitigation of cellular damage remain incompletely elucidated. In this study, we reveal the pivotal role of RNA-binding motif protein 46 (RBM46) in ESCs, acting as a direct post transcriptional regulator of ROS levels by modulating BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Bnip3) mRNA expression. Rbm46 knockout lead to diminished mitochondrial autophagy, culminating in elevated ROS within ESCs, disrupting the delicate balance required for healthy self-renewal. These findings provide insights into a novel mechanism governing ROS regulation in ESCs.

Disrupted mossy fiber connections from defective embryonic neurogenesis contribute to SOX11-associated schizophrenia.

Abnormal mossy fiber connections in the hippocampus have been implicated in schizophrenia. However, it remains unclear whether this abnormality in the patients is genetically determined and whether it contributes to the onset of schizophrenia. Here, we showed that iPSC-derived hippocampal NPCs from schizophrenia patients with the A/A allele at SNP rs16864067 exhibited abnormal NPC polarity, resulting from the downregulation of SOX11 by this high-risk allele. In the SOX11-deficient mouse brain, abnormal NPC polarity was also observed in the hippocampal dentate gyrus, and this abnormal NPC polarity led to defective hippocampal neurogenesis-specifically, irregular neuroblast distribution and disrupted granule cell morphology. As granule cell synapses, the mossy fiber pathway was disrupted, and this disruption was resistant to activity-induced mossy fiber remodeling in SOX11 mutant mice. Moreover, these mutant mice exhibited diminished PPI and schizophrenia-like behaviors. Activation of hippocampal neurogenesis in the embryonic brain, but not in the adult brain, partially alleviated disrupted mossy fiber connections and improved schizophrenia-related behaviors in mutant mice. We conclude that disrupted mossy fiber connections are genetically determined and strongly correlated with schizophrenia-like behaviors in SOX11-deficient mice. This disruption may reflect the pathological substrate of SOX11-associated schizophrenia.

Differentiation of adult human retinal pigment epithelial cells into dopaminergic-like cells in vitro and in the recipient monkey brain.

BACKGROUND: Cell therapy is proposed to be a potential treatment for Parkinson's disease (PD). Although fetal retinal pigment epithelial (RPE) cells have been tested in trials for treating PD patients, controversy has been raised over the issue of whether such cells can be reprogrammed into dopamine-producing cells for therapeutic efficacy. Here, we aim to investigate whether adult human RPE cells can be reprogrammed into dopamine-producing cells both in vitro and in the recipient monkey brain. METHODS: The RPE layer was isolated from frozen posterior eyeball tissue after penetrating keratoplasty surgery. The tumorigenicity of RPE cells was examined by G-banding and a tumor formation assay in nude mice. Immunogenicity was measured using a one-way mixed lymphocyte reaction (MLR) assay. Dopamine-production in chemically reprogrammed RPE cells was measured by HPLC. Finally, RPE cells were grafted into the brains of monkeys with MPTP-induced PD in order to investigate the potential of such cells treating PD patients in the future. RESULTS: RPE cell lines have been successively established from adult human eye tissues. Such cells can be chemically reprogrammed into dopamine-producing cells in vitro. Moreover, after being grafted into the brain caudate putamen of monkeys with MPTP-induced PD, RPE cells became tyrosine hydroxylase-positive cells, and recipient PD monkeys showed significant improvement of clinical conditions. CONCLUSIONS: This preclinical study using a primate model indicates that human adult RPE cells could be a potential cell source for the treatment of PD in the future.

Enhanced Immunological Tolerance by HLA-G1 from Neural Progenitor Cells (NPCs) Derived from Human Embryonic Stem Cells (hESCs).

BACKGROUND: Despite the great potential of utilizing human embryonic stem cells (hESCs)-derived cells as cell source for transplantation, these cells were often rejected during engraftment by the immune system due to adaptive immune response. METHODS: We first evaluated HLA-G expression level in both hESCs and differentiated progenitor cells. After that, we generated modified hESC lines that over-express HLA-G1 using lentiviral infection with the construct contains both HLA-G1 and GFP tag. The lentivirus was first produced by co-transfecting HLA-G1 expressing lentiviral vector together with packaging vectors into packaging cell line 293T. Then the produced virus was used for the infection of selected hESC lines. We characterized the generated cell lines phenotype, including pluripotency and self-renewal abilities, as well as immune tolerance ability by mixed lymphocyte reaction (MLR) and cytotoxicity assays. RESULTS: Although the hESCs do not express high levels of HLA-G1, over-expression of HLA-G1 in hESCs still retains their stem cell characteristics as determined by retaining the expression levels of OCT4 and SOX2, two critical transcriptional factors for stem cell function. Furthermore, the HLA-G1 overexpressing hESCs retain the self-renewal and pluripotency characteristics of stem cells, which can differentiate into different types of cells, including pigment cells, smooth muscle cells, epithelia-like cells, and NPCs. After differentiation, the differentiated cells including NPCs retain the high levels of HLA-G1 protein. In comparison with conventional NPCs, these HLA-G1 positive NPCs have enhanced immune tolerance ability. CONCLUSIONS: Ectopic expression of HLA-G1, a non-classical major histocompatibility complex class I (MHC I) antigen that was originally discovered involving in engraftment tolerance during pregnancy, can enhance the immunological tolerance in differentiated neural progenitor cells (NPCs). Our study shows that stably overexpressing HLA-G1 in hESCs might be a feasible strategy for enhancing the engraftment of NPCs during transplantation.

BTG/Tob family members Tob1 and Tob2 inhibit proliferation of mouse embryonic stem cells via Id3 mRNA degradation.

The mammalian BTG/Tob family is a group of proteins with anti-proliferative ability, and there are six members including BTG1, BTG2/PC3/Tis21, BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2. Among them, Tob subfamily members, specifically Tob1/Tob and Tob2, have the most extensive C-terminal regions. As previously reported, overexpression of BTG/Tob proteins is associated with the inhibition of G1 to S-phase cell cycle progression and decreased cell proliferation in a variety of cell types. Tob subfamily proteins have similar anti-proliferative effects on cell cycle progression in cultured tumor cells. An important unresolved question is whether or not they have function in rapidly proliferating cells, such as embryonic stem cells (ESCs). Tob1 and Tob2 were expressed ubiquitously in mouse ESCs (mESCs), suggesting a possible role in early embryonic development and mESCs. To address the above question and explore the possible functions of the Tob subfamily in ESCs, we established ESCs from different genotypic knockout inner cell mass (ICM). We found that Tob1(-/-), Tob2(-/-), and Tob1/2 double knockout (DKO, Tob1(-/-) & Tob2(-/-)) ESCs grew faster than wild type (WT) ESCs without losing pluripotency, and we provide a possible mechanistic explanation for these observations: Tob1 and Tob2 inhibit the cell cycle via degradation of Id3 mRNA, which is a set of directly targeted genes of BMP4 signaling in mESCs that play critical roles in the maintenance of ESC properties. Together, our data suggest that BTG/Tob family protein Tob1 and Tob2 regulation cell proliferation does not compromise the basic properties of mESCs.

Lysophosphatidic acid accelerates lung fibrosis by inducing differentiation of mesenchymal stem cells into myofibroblasts.

Lung fibrosis is characterized by vascular leakage and myofibroblast recruitment, and both phenomena are mediated by lysophosphatidic acid (LPA) via its type-1 receptor (LPA1). Following lung damage, the accumulated myofibroblasts activate and secrete excessive extracellular matrix (ECM), and form fibrotic foci. Studies have shown that bone marrow-derived cells are an important source of myofibroblasts in the fibrotic organ. However, the type of cells in the bone marrow contributing predominantly to the myofibroblasts and the involvement of LPA-LPA1 signalling in this is yet unclear. Using a bleomycin-induced mouse lung-fibrosis model with an enhanced green fluorescent protein (EGFP) transgenic mouse bone marrow replacement, we first demonstrated that bone marrow derived-mesenchymal stem cells (BMSCs) migrated markedly to the bleomycin-injured lung. The migrated BMSC contributed significantly to α-smooth muscle actin (α-SMA)-positive myofibroblasts. By transplantation of GFP-labelled human BMSC (hBMSC) or EGFP transgenic mouse BMSC (mBMSC), we further showed that BMSC might be involved in lung fibrosis in severe combined immune deficiency (SCID)/Beige mice induced by bleomycin. In addition, using quantitative-RT-PCR, western blot, Sircol collagen assay and migration assay, we determined the underlying mechanism was LPA-induced BMSC differentiation into myofibroblast and the secretion of ECM via LPA1. By employing a novel LPA1 antagonist, Antalpa1, we then showed that Antalpa1 could attenuate lung fibrosis by inhibiting both BMSC differentiation into myofibroblast and the secretion of ECM. Collectively, the above findings not only further validate LPA1 as a drug target in the treatment of pulmonary fibrosis but also elucidate a novel pathway in which BMSCs contribute to the pathologic process.

Sox2 protects neural stem cells from apoptosis via up-regulating survivin expression.

The transcription factor Sox2 [SRY (sex-determining region Y)-box 2] is essential for the regulation of self-renewal and homoeostasis of NSCs (neural stem cells) during brain development. However, the downstream targets of Sox2 and its underlying molecular mechanism are largely unknown. In the present study, we found that Sox2 directly up-regulates the expression of survivin, which inhibits the mitochondria-dependent apoptotic pathway in NSCs. Although overexpression of Sox2 elevates survivin expression, knockdown of Sox2 results in a decrease in survivin expression, thereby initiating the mitochondria-dependent apoptosis related to caspase 9 activation. Furthermore, cell apoptosis owing to knockdown of Sox2 can be rescued by ectopically expressing survivin in NSCs as well as in the mouse brain, as demonstrated by an in utero-injection approach. In short, we have found a novel Sox2/survivin pathway that regulates NSC survival and homoeostasis, thus revealing a new mechanism of brain development, neurological degeneration and such aging-related disorders.

Stem cell signaling as a target for novel drug discovery: recent progress in the WNT and Hedgehog pathways.

One of the most exciting fields in biomedical research over the past few years is stem cell biology, and therapeutic application of stem cells to replace the diseased or damaged tissues is also an active area in development. Although stem cell therapy has a number of technical challenges and regulatory hurdles to overcome, the use of stem cells as tools in drug discovery supported by mature technologies and established regulatory paths is expected to generate more immediate returns. In particular, the targeting of stem cell signaling pathways is opening up a new avenue for drug discovery. Aberrations in these pathways result in various diseases, including cancer, fibrosis and degenerative diseases. A number of drug targets in stem cell signaling pathways have been identified. Among them, WNT and Hedgehog are two most important signaling pathways, which are the focus of this review. A hedgehog pathway inhibitor, vismodegib (Erivedge), has recently been approved by the US FDA for the treatment of skin cancer, while several drug candidates for the WNT pathway are entering clinical trials. We have discovered that the stem cell signaling pathways respond to traditional Chinese medicines. Substances isolated from herbal medicine may act specifically on components of stem cell signaling pathways with high affinities. As many of these events can be explained through molecular interactions, these phenomena suggest that discovery of stem cell-targeting drugs from natural products may prove to be highly successful.

Clinical phase I/II trial of SVF therapy for cartilage regeneration: A cellular therapy with novel 3D MRI imaging for evaluating chondral defect of knee osteoarthritis.

Background: The clinical applications of stromal vascular fraction (SVF) therapy for osteoarthritis (OA) have attracted academic and clinical attention. However, data of the effects of stromal vascular fraction therapy on regeneration of degenerated cartilage are limited in the literature. Meanwhile, there is a great need for a simple and non-invasive evaluation method to analyze the changes of joint cartilage qualitatively and quantitatively in clinical trials. This study entitled "stromal vascular fraction Therapy for Human Knee Osteoarthritis" was registered in ClinicalTrial.gov # NCT05019378. Materials and Methods: We designed and conducted a single center, open labeled clinical phase I/II study, and 6 osteoarthritis patients with both knee cartilage defect I-II were enrolled in this study. The two knees of each patient were randomly assigned to autologous stromal vascular fraction treatment group or non-treatment control group to evaluate the safety and therapeutic effect of stromal vascular fraction therapy for human knee osteoarthritis. We have also established a novel protocol to provide 3D MRI imaging for human knee cartilage enabling us to qualitatively and quantitatively evaluate cartilage degeneration and regeneration in this study. Results: The qualitative and quantitative evaluation of 3D Magnetic Resonance Imaging (MRI) imaging of knee cartilage demonstrated that the stromal vascular fraction therapy reduced the cartilage defects; and significant increase of cartilage value both in defect cartilage area and whole cartilage area of treated group and significant increase of thickness and area of both femoral and tibia cartilage in vertical sections of the stromal vascular fraction treated Group at 12 and 24 W post treatment in cartilage defect I-II osteoarthritis patients. Conclusion: This clinical phase I/II study indicated that stromal vascular fraction therapy is a safe clinical procedure and provided evidence that the stromal vascular fraction therapy significantly facilitated cartilage regeneration, opening the opportunity to a phase III trial investigating authentic efficacy of the procedure. This study is the first qualitative and quantitative evaluation of the efficacy of autologous stromal vascular fraction cellular therapy on cartilage regeneration. Through early and definite diagnosis of knee osteoarthritis patients, and providing safe and efficient therapy to facilitate cartilage regeneration, we will be able to control or reverse cartilage degeneration and completely change the epidemiology of osteoarthritis worldwide.

Recognition and Analysis of Sports on Mental Health Based on Deep Learning.

This paper presents the purpose of sport recognition of mental health for users and analyzes and studies the recognition of mental health by sports based on deep learning. The recognition model of sport mental health state composed of data layer, logic layer and display layer is built. After fusing human health data with deep learning algorithm, the feature of human health mutual information is extracted, the feature into the recognition model of mental health state is inputted, and the recognition results of sport mental health mode after forward and reverse operation are outputted. The recognition data of sports on mental health status are obtained, which correspond to the link flowing through during multi-level transmission, calibrate the multi-level transmission point, and fuse and process the recognition information of sports on mental health status. The experimental results show that the loss value of the research method when analyzing the effect of sports on mental health enhancement is the smallest, the output result is reliable, can effectively improve the body mass index (BMI) of the human body, has the most controllable amount of data, and has good performance.

Cancer Cells Evade Stress-Induced Apoptosis by Promoting HSP70-Dependent Clearance of Stress Granules.

The formation of stress granules (SG) is regarded as a cellular mechanism to temporarily limit protein synthesis and prevent the unfolding of proteins in stressed cells. It has been noted that SG formation can promote the survival of stressed cells. Paradoxically, however, persistent SGs could cause cell death. The underlying molecular mechanism that affects the relationship between SG dynamics and cellular states is not fully understood. Here we found that SG dynamics in cancer cells differ significantly from those in normal cells. Specifically, prolonged stress caused the formation of persistent SGs and consequently resulted in apoptosis in the normal cells. By contrast, cancer cells resolved SGs and survived the prolonged stress. Regarding the mechanism, the knockdown of HSP70 or the inhibition of the HSP70s' ATPase activity caused defective SG clearance, leading to apoptosis in otherwise healthy cancer cells. On the other hand, the knockout of G3BPs to block the formation of SGs allowed cancer cells to escape from the HSP70 inhibition-induced apoptosis. Given the observation that SG dynamics were barely affected by the inhibition of autophagy or proteasome, we propose that SG dynamics are regulated mainly by HSP70-mediated refolding of the unfolded proteins or their removal from SGs. As a result, cancer cells evade stress-induced apoptosis by promoting the HSP70-dependent SG clearance.

Hepatoblast-like progenitor cells derived from embryonic stem cells can repopulate livers of mice.

BACKGROUND & AIMS: Hepatocyte-like cells can be derived from pluripotent stem cells such as embryonic stem (ES) cells, but ES cell-derived hepatic cells with extensive capacity to repopulate liver have not been identified. We aimed to identify and purify ES cell-derived hepatoblast-like progenitor cells and to explore their capacity for liver repopulation in mice after in vitro expansion. METHODS: Unmanipulated mouse ES cells were cultured under defined conditions and allowed to undergo stepwise hepatic differentiation. The derived hepatic cells were examined by morphologic, fluorescence-activated cell sorting, gene expression, and clonal expansion analyses. The capacities of ES cell-derived hepatic progenitor cells to repopulate liver were investigated in mice that were deficient in fumarylacetoacetate hydrolase (Fah) (a model of liver injury). RESULTS: Mouse ES cells were induced to differentiate into a population that contained hepatic progenitor cells; this population included cells that expressed epithelial cell adhesion molecule (EpCAM) but did not express c-Kit. Clonal hepatic progenitors that arose from single c-Kit(-)EpCAM(+) cells could undergo long-term expansion and maintain hepatoblast-like characteristics. Enriched c-Kit(-)EpCAM(+) cells and clonally expanded hepatic progenitor cells repopulated the livers of Fah-deficient mice without inducing tumorigenesis. CONCLUSIONS: ES cell-derived c-Kit(-)EpCAM(+) cells contain a population of hepatoblast-like progenitor cells that can repopulate livers of mice.

The EGF receptor-sox2-EGF receptor feedback loop positively regulates the self-renewal of neural precursor cells.

The transcriptional factor Sox2 and epidermal growth factor receptor (Egfr)-mediated signaling are both required for self-renewal of neural precursor cells (NPCs). However, the mechanism by which these factors coordinately regulate this process is largely unknown. Here we show that Egfr-mediated signaling promotes Sox2 expression, which in turn binds to the Egfr promoter and directly upregulates Egfr expression. Knockdown of Sox2 by RNA interference downregulates Egfr expression and attenuates colony formation of NPCs, whereas overexpression of Sox2 elevates Egfr expression and promotes NPC self-renewal. Moreover, the effect of Sox2 on NPC self-renewal is completely inhibited by AG1478, a specific inhibitor for Egfr; it is also inhibited by LY294002 and U0126, selective antagonists for phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (Erk1/2), respectively. Collectively, we conclude that NPC self-renewal is enhanced through a novel cellular feedback loop with mutual regulation of Egfr and Sox2.

Rapid and efficient reprogramming of human amnion-derived cells into pluripotency by three factors OCT4/SOX2/NANOG.

Reprogramming human somatic cells to pluripotency represents a valuable resource for research aiming at the development of in vitro models for human diseases and regenerative medicines to produce patient-specific induced pluripotent stem (iPS) cells. Seeking appropriate cell resources for higher efficiency and reducing the risk of viral transgene activation, especially oncogene activation, are of significance for iPS cell research. In this study, we tested whether human amnion-derived cells (hADCs) could be rapidly and efficiently reprogrammed into iPS cells by the defined factors: OCT4/SOX2/NANOG. hADCs from normal placenta were isolated and cultured. The 3rd passage cells were infected with the lentiviral vectors for the delivery of OCT4, SOX2, and NANOG. Afterwards, the generated iPSCs were identified by morphology, pluripotency markers, global gene expression profiles, and epigenetic status both in vitro and in vivo. The results showed that we were able to reprogram hADCs by the defined factors (OCT4/SOX2/NANOG). The efficiency was significantly high (about 0.1%), and the typical colonies appeared on the 9th day after infection. They were similar to human embryonic stem (ES) cells in morphology, proliferation, surface markers, gene expression, and the epigenetic status of pluripotent cell-specific genes. Furthermore, these cells were able to differentiate into various cell types of all three germ layers both in vitro and in vivo. These results demonstrate that hADCs were an ideal somatic cell resource for the rapid and efficient generation of iPS cells by OCT4/SOX2/NANOG.

Alternative translation of OCT4 by an internal ribosome entry site and its novel function in stress response.

OCT4 is a pivotal transcription factor in maintaining the pluripotency and self-renewal capacities of embryonic stem (ES) cells. Human OCT4 can generate two isoforms by alternative splicing, termed OCT4A and OCT4B. OCT4A confers the stemness properties of ES cells, whereas the function of OCT4B is unknown. We present here the diverse protein products and a novel function of OCT4 gene. A single OCT4B mRNA can encode three isoforms by alternative translation initiation at AUG and CUG start codons, respectively. A putative internal ribosome entry site (IRES) has been identified in OCT4B mRNA accounting for the translation mechanism. The OCT4B-190 is upregulated under stress conditions and it may protect cell against apoptosis under stress. This work evokes the significance to distinguish the biological function of the protein products of OCT4. The OCT4 gene, by the regulation of alternative splicing and alternative translation initiation, may carry out more crucial roles in many biological events.

Homing of bone marrow mesenchymal stem cells mediated by sphingosine 1-phosphate contributes to liver fibrosis.

BACKGROUND/AIMS: Myofibroblasts play a central role in the pathogenesis of liver fibrosis. Myofibroblasts of bone marrow (BM) origin have recently been identified in fibrotic liver. However, little is known about the mechanism that controls their mobilization in vivo. Here we confirmed that BM mesenchymal stem cells (BMSCs) can migrate to the damaged liver and differentiate into myofibroblasts. We also investigated the mechanism underlying the homing of BMSCs after liver injury. METHODS: ICR mice were lethally irradiated and received BM transplants from enhanced green fluorescent protein transgenic mice. Carbon tetrachloride or bile duct ligation was used to induce liver fibrosis. The fibrotic liver tissue was examined by immunofluorescent staining to identify BM-derived myofibroblasts. RESULTS: BMSCs contributed significantly to myofibroblast population in fibrotic liver. Moreover, analysis in vivo and in vitro suggested that homing of BMSCs to the damaged liver was in response to sphingosine 1-phosphate (S1P) gradient between liver and BM. Furthermore, S1P receptor type 3 (S1P3) was required for migration of BMSCs triggered by S1P. CONCLUSIONS: S1P mediates liver fibrogenesis through homing of BMSCs via S1P3 receptor, which may represent a novel therapeutic target in liver fibrosis through inhibiting S1P formation and/or receptor activation.

Oct4 is expressed in Nestin-positive cells as a marker for pancreatic endocrine progenitor.

There are abundant progenitor cells in the developing pancreas, but molecular markers for these cells are lacking. Octamer-binding transcription factor-4 (Oct4) is an important transcription factor for keeping the features of self-renewal and pluripotency of embryonic stem cells. It's well known that Oct4, as a totipotent stem cells marker, just is expressed in totipotent stem cells. In the present study, we collected ten human fetal pancreases, and found that Oct4 mRNA and protein were expressed in human fetal pancreas samples by RT-PCR, western blot and immunohistochemistry assays. Using double-staining, we demonstrated that Oct4 was not co-expressed with Chromogranin A (a peptide expressed in endocrine cells), but partially co-expressed with Ngn3 (a transcription factor expressed in pancreatic endocrine precursor cells) and Nestin (a intermediate filament, Nestin-positive cells isolated from islets can be induced to express insulin) in human fetal pancreases. Indeed, we prepared Nestin-positive cells from human fetal pancreas by cell selection, and found that these cells expressed Oct4 and Ngn3. The Nestin-positive cells displayed a rapid duplication and could differentiate into osteoblasts, fat and endocrine cells in vitro. These results indicated that the Nestin-positive cells in the fetal age should be pancreatic progenitor cells. Overall, our study suggested that Oct4 was a marker for pancreatic endocrine progenitor.

Pax6 directly modulate Sox2 expression in the neural progenitor cells.

Pax6 is a key regulator in the neuronal fate determination as well as the proliferation of neural stem cells, but the mechanisms are still unknown. Our study shows that Pax6 regulate the proliferation of neural progenitor cells of cortical subventricular zone, through direct modulation of the Sox2 expression during the late developmental stage in mice. We found a dramatic decrease in the number of Sox2+ neural progenitor cells in the subventricular zone of E18.5 Pax6(-/-) mice. We confirmed that Pax6 could bind to the Sox2 promoter by chromatin immunoprecipitation assay and activate Sox2 expression by a luciferase reporter gene assay. Moreover, neural progenitors isolated from the Pax6(-/-) embryos showed a decreased neurosphere formation as well as proliferation.

Hepatocyte growth factor promotes proliferation and migration in immortalized progenitor cells.

Hepatocyte growth factor (HGF) and its receptor c-Met are widely expressed in the developing and adult brain. However, little is known about the role of HGF during the development of the human dopaminergic neuronal system. We have established telomerase-immortalized dopaminergic progenitor cells isolated from the fetal striatum that express markers for neural progenitor cells and tyrosine hydroxylase. We show that the cells were able to differentiate into dopaminergic neurons and release dopamine. Exogenous HGF-induced proliferation was inhibited by U0126, whereas migration was completely blocked by LY294002. Study demonstrates that HGF regulates the proliferation and migration of dopaminergic progenitor cells. Modulating dopaminergic progenitor cells in the striatum may prove to be a new approach for treating Parkinson's disease.