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Neural differentiation of brain-derived neurotrophic factor-expressing human umbilical cord blood-derived mesenchymal stem cells in culture via TrkB-mediated ERK and β-catenin phosphorylation and following transplantation into the developing brain.
Cell Transplant 2011; 20(11-12):1855-66CT

Abstract

The ability of mesenchymal stem cells (MSCs) to differentiate into neural cells makes them potential replacement therapeutic candidates in neurological diseases. Presently, overexpression of brain-derived neurotrophic factor (BDNF), which is crucial in the regulation of neural progenitor cell differentiation and maturation during development, was sufficient to convert the mesodermal cell fate of human umbilical cord blood-derived MSCs (hUCB-MSCs) into a neuronal fate in culture, in the absence of specialized induction chemicals. BDNF overexpressing hUCB-MSCs (MSCs-BDNF) yielded an increased number of neuron-like cells and, surprisingly, increased the expression of neuronal phenotype markers in a time-dependent manner compared with control hUCB-MSCs. In addition, MSCs-BDNF exhibited a decreased labeling for MSCs-related antigens such as CD44, CD73, and CD90, and decreased potential to differentiate into mesodermal lineages. Phosphorylation of the receptor tyrosine kinase B (TrkB), which is a receptor of BDNF, was increased significantly in MSC-BDNF. BDNF overexpression also increased the phosphorylation of β-catenin and extracellular signal-regulated kinases (ERKs). Inhibition of TrkB availability by treatment with the TrkB-specific inhibitor K252a blocked the BDNF-stimulated phosphorylation of β-catenin and ERKs, indicating the involvement of both the β-catenin and ERKs signals in the BDNF-stimulated and TrkB-mediated neural differentiation of hUCB-MSCs. Reduction of β-catenin availability using small interfering RNA-mediated gene silencing inhibited ERKs phosphorylation. However, β-catenin activation was maintained. In addition, inhibition of β-catenin and ERKs expression levels abrogated the BDNF-stimulated upregulation of neuronal phenotype markers. Furthermore, MSC-BDNF survived and migrated more extensively when grafted into the lateral ventricles of neonatal mouse brain, and differentiated significantly into neurons in the olfactory bulb and periventricular astrocytes. These results indicate that BDNF induces the neural differentiation of hUCB-MSCs in culture via the TrkB-mediated phosphorylation of ERKs and β-catenin and following transplantation into the developing brain.

Authors+Show Affiliations

Department of Biomedical Science, College of Medicine, The Catholic University of Korea, Seoul, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21375801

Citation

Lim, Jung Yeon, et al. "Neural Differentiation of Brain-derived Neurotrophic Factor-expressing Human Umbilical Cord Blood-derived Mesenchymal Stem Cells in Culture Via TrkB-mediated ERK and Β-catenin Phosphorylation and Following Transplantation Into the Developing Brain." Cell Transplantation, vol. 20, no. 11-12, 2011, pp. 1855-66.
Lim JY, Park SI, Kim SM, et al. Neural differentiation of brain-derived neurotrophic factor-expressing human umbilical cord blood-derived mesenchymal stem cells in culture via TrkB-mediated ERK and β-catenin phosphorylation and following transplantation into the developing brain. Cell Transplant. 2011;20(11-12):1855-66.
Lim, J. Y., Park, S. I., Kim, S. M., Jun, J. A., Oh, J. H., Ryu, C. H., ... Jeun, S. S. (2011). Neural differentiation of brain-derived neurotrophic factor-expressing human umbilical cord blood-derived mesenchymal stem cells in culture via TrkB-mediated ERK and β-catenin phosphorylation and following transplantation into the developing brain. Cell Transplantation, 20(11-12), pp. 1855-66. doi:10.3727/096368910X557236.
Lim JY, et al. Neural Differentiation of Brain-derived Neurotrophic Factor-expressing Human Umbilical Cord Blood-derived Mesenchymal Stem Cells in Culture Via TrkB-mediated ERK and Β-catenin Phosphorylation and Following Transplantation Into the Developing Brain. Cell Transplant. 2011;20(11-12):1855-66. PubMed PMID: 21375801.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neural differentiation of brain-derived neurotrophic factor-expressing human umbilical cord blood-derived mesenchymal stem cells in culture via TrkB-mediated ERK and β-catenin phosphorylation and following transplantation into the developing brain. AU - Lim,Jung Yeon, AU - Park,Sang In, AU - Kim,Seong Muk, AU - Jun,Jin Ae, AU - Oh,Ji Hyeon, AU - Ryu,Chung Hun, AU - Jeong,Chang Hyun, AU - Park,Sun Hwa, AU - Park,Soon A, AU - Oh,Wonil, AU - Chang,Jong Wook, AU - Jeun,Sin-Soo, Y1 - 2011/03/04/ PY - 2011/3/8/entrez PY - 2011/3/8/pubmed PY - 2013/6/20/medline SP - 1855 EP - 66 JF - Cell transplantation JO - Cell Transplant VL - 20 IS - 11-12 N2 - The ability of mesenchymal stem cells (MSCs) to differentiate into neural cells makes them potential replacement therapeutic candidates in neurological diseases. Presently, overexpression of brain-derived neurotrophic factor (BDNF), which is crucial in the regulation of neural progenitor cell differentiation and maturation during development, was sufficient to convert the mesodermal cell fate of human umbilical cord blood-derived MSCs (hUCB-MSCs) into a neuronal fate in culture, in the absence of specialized induction chemicals. BDNF overexpressing hUCB-MSCs (MSCs-BDNF) yielded an increased number of neuron-like cells and, surprisingly, increased the expression of neuronal phenotype markers in a time-dependent manner compared with control hUCB-MSCs. In addition, MSCs-BDNF exhibited a decreased labeling for MSCs-related antigens such as CD44, CD73, and CD90, and decreased potential to differentiate into mesodermal lineages. Phosphorylation of the receptor tyrosine kinase B (TrkB), which is a receptor of BDNF, was increased significantly in MSC-BDNF. BDNF overexpression also increased the phosphorylation of β-catenin and extracellular signal-regulated kinases (ERKs). Inhibition of TrkB availability by treatment with the TrkB-specific inhibitor K252a blocked the BDNF-stimulated phosphorylation of β-catenin and ERKs, indicating the involvement of both the β-catenin and ERKs signals in the BDNF-stimulated and TrkB-mediated neural differentiation of hUCB-MSCs. Reduction of β-catenin availability using small interfering RNA-mediated gene silencing inhibited ERKs phosphorylation. However, β-catenin activation was maintained. In addition, inhibition of β-catenin and ERKs expression levels abrogated the BDNF-stimulated upregulation of neuronal phenotype markers. Furthermore, MSC-BDNF survived and migrated more extensively when grafted into the lateral ventricles of neonatal mouse brain, and differentiated significantly into neurons in the olfactory bulb and periventricular astrocytes. These results indicate that BDNF induces the neural differentiation of hUCB-MSCs in culture via the TrkB-mediated phosphorylation of ERKs and β-catenin and following transplantation into the developing brain. SN - 1555-3892 UR - https://www.unboundmedicine.com/medline/citation/21375801/Neural_differentiation_of_brain_derived_neurotrophic_factor_expressing_human_umbilical_cord_blood_derived_mesenchymal_stem_cells_in_culture_via_TrkB_mediated_ERK_and_β_catenin_phosphorylation_and_following_transplantation_into_the_developing_brain_ L2 - http://journals.sagepub.com/doi/full/10.3727/096368910X557236?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -