TY - JOUR
T1 - Intranigral Transplantation of Epigenetically Induced BDNF-Secreting Human Mesenchymal Stem Cells
T2 - Implications for Cell-Based Therapies in Parkinson's Disease
AU - Somoza, Rodrigo
AU - Juri, Carlos
AU - Baes, Mauricio
AU - Wyneken, Ursula
AU - Rubio, Francisco Javier
N1 - Funding Information:
Financial disclosure: This work was supported in part by grants to F.J.R. from the Fundacion Andes C-14060/60 , Universidad del Desarrollo 80.11.037 , and Anillo ACT09_2006 (to U.W.).
PY - 2010/11
Y1 - 2010/11
N2 - It is thought that the ability of human mesenchymal stem cells (hMSC) to deliver neurotrophic factors might be potentially useful for the treatment of neurodegenerative disorders. The aim of the present study was to characterize signals and/or molecules that regulate brain-derived neurotrophic factor (BDNF) protein expression/delivery in hMSC cultures and evaluate the effect of epigenetically generated BDNF-secreting hMSC on the intact and lesioned substantia nigra (SN). We tested 4 different culture media and found that the presence of fetal bovine serum (FBS) decreased the expression of BDNF, whereas exogenous addition of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) to serum-free medium was required to induce BDNF release (125 ± 12 pg/day/106 cells). These cells were called hM(N)SC. Although the induction medium inhibited the expression of alpha smooth muscle actin (ASMA), an hMSC marker, and increased the nestin-positive subpopulation of hMSC cultures, the ability to express BDNF was restricted to the nestin-negative subpopulation. One week after transplantation into the SN, the human cells integrated into the surrounding tissue, and some showed a dopaminergic phenotype. We also observed the activation of Trk receptors for neurotrophic factors around the implant site, including the BDNF receptor TrkB. When we transplanted these cells into the unilateral lesioned SN induced by striatal injection of 6-hydroxydopamine (6-OHDA), a significant hypertrophy of nigral tyrosine hydroxylase (TH)+ cells, an increase of striatal TH-staining and stabilization of amphetamine-induced motor symptoms were observed. Therefore, hMSC cultures exposed to the described induction medium might be highly useful as a vehicle for neurotrophic delivery to the brain and specifically are strong candidates for future therapeutic application in Parkinson's disease.
AB - It is thought that the ability of human mesenchymal stem cells (hMSC) to deliver neurotrophic factors might be potentially useful for the treatment of neurodegenerative disorders. The aim of the present study was to characterize signals and/or molecules that regulate brain-derived neurotrophic factor (BDNF) protein expression/delivery in hMSC cultures and evaluate the effect of epigenetically generated BDNF-secreting hMSC on the intact and lesioned substantia nigra (SN). We tested 4 different culture media and found that the presence of fetal bovine serum (FBS) decreased the expression of BDNF, whereas exogenous addition of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) to serum-free medium was required to induce BDNF release (125 ± 12 pg/day/106 cells). These cells were called hM(N)SC. Although the induction medium inhibited the expression of alpha smooth muscle actin (ASMA), an hMSC marker, and increased the nestin-positive subpopulation of hMSC cultures, the ability to express BDNF was restricted to the nestin-negative subpopulation. One week after transplantation into the SN, the human cells integrated into the surrounding tissue, and some showed a dopaminergic phenotype. We also observed the activation of Trk receptors for neurotrophic factors around the implant site, including the BDNF receptor TrkB. When we transplanted these cells into the unilateral lesioned SN induced by striatal injection of 6-hydroxydopamine (6-OHDA), a significant hypertrophy of nigral tyrosine hydroxylase (TH)+ cells, an increase of striatal TH-staining and stabilization of amphetamine-induced motor symptoms were observed. Therefore, hMSC cultures exposed to the described induction medium might be highly useful as a vehicle for neurotrophic delivery to the brain and specifically are strong candidates for future therapeutic application in Parkinson's disease.
KW - Mesenchymal stem cell transplantation
KW - Neurotrophins
KW - Substantia nigra
KW - Trk receptors
KW - Unilateral 6-hydroxydopamine lesion
KW - Mesenchymal stem cell transplantation
KW - Neurotrophins
KW - Substantia nigra
KW - Trk receptors
KW - Unilateral 6-hydroxydopamine lesion
UR - http://www.scopus.com/inward/record.url?scp=77957751719&partnerID=8YFLogxK
U2 - 10.1016/j.bbmt.2010.06.006
DO - 10.1016/j.bbmt.2010.06.006
M3 - Article
C2 - 20542127
AN - SCOPUS:77957751719
SN - 1083-8791
VL - 16
SP - 1530
EP - 1540
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 11
ER -
