Human neural progenitor cells over-expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson's disease

Growth factors such as glial cell line-derived neurotrophic factor (GDNF) have been shown to prevent neurodegeneration and promote regeneration in many animal models of Parkinson's disease (PD). Insulin-like growth factor 1 (IGF-1) is also known to have neuroprotective effects in a number of disease models but has not been extensively studied in models of PD. We produced human neural progenitor cells (hNPC) releasing either GDNF or IGF-1 and transplanted them into a rat model of PD. hNPC secreting either GDNF or IGF-1 were shown to significantly reduce amphetamine-induced rotational asymmetry and dopamine neuron loss when transplanted 7 days after a 6-hydroxydopamine (6-OHDA) lesion. Neither untransduced hNPC nor a sham transplant had this effect suggesting GDNF and IGF-1 release was required. Interestingly, GDNF, but not IGF-1, was able to protect or regenerate tyrosine hydroxylase-positive fibers in the striatum. In contrast, IGF-1, but not GDNF, significantly increased the overall survival of hNPC both in vitro and following transplantation. This suggests a dual role of IGF-1 to both increase hNPC survival after transplantation and exert trophic effects on degenerating dopamine neurons in this rat model of PD.     

外源性SDF-1α和GDNF基因在恒河猴骨髓基质细胞内的稳定表达

目的 构建携带人基质细胞衍生因子-1α(SDF-1α)和胶质细胞源神经营养因子(GDNF)基因的真核表达质粒pBudCE4.1-SDF-1α-GDNF,转染恒河猴骨髓基质细胞(BMSCs),观察外源性SDF-1α和GDNF基因在BMSCs中的表达情况. 方法 应用基因重组技术,从cDNA文库获得GDNF和SDF-1α基因,重组到pBudCE4.1双表达载体上.pBudCE4.1-SDF-1α-GDNF经脂质体转染培养的恒河猴BMSCs,48 h后行GDNF和SDF-1α Western blot和免疫组化检测. 结果 酶切、PCR和DNA序列鉴定均证实插入基因片段的正确性;48 h后行West blot和免疫组化证实GDNF和SDF-1α在细胞内能有效表达.pBudCE4.1-GDNF-SDF-1α转染BMSCs表达的GDNF和SDF-1α蛋白的量是阴性对照细胞的10倍和6倍. 结论 双基因真核表达质粒DBudCE4.1-SDF -1α-GDNF转染至恒河猴BMSCs后,SDF-1α和GDNF基因在BMSCs内能有效表达,为BMSCs携带SDF-1α和GDNF双基因自体移植治疗相关疾病奠定了基础.     

GDNF but not BDNF is increased in cerebrospinal fluid in amyotrophic lateral sclerosis

Cerebrospinal fluid from 15 patients with ALS and 11 controls without neurological disease were analysed for levels of the neurotrophic factors BDNF and GDNF. Analyses were performed using a sensitive sandwich immunoassay (ELISA). There was no significant difference in BDNF levels between the ALS patients and the control subjects studied. Measurable levels of GDNF were found in 12 out of 15 ALS samples. GDNF was not detected in CSF from any of the control subjects. The finding of increased CSF levels of GDNF in ALS compared to controls, together with earlier findings of increased expression of GDNF mRNA in muscle in ALS, indicates that the capacity to synthesize GDNF is enhanced in this disorder.     

Increased expression of glial cell line-derived neurotrophic factor mRNA in muscle biopsies from patients with amyotrophic lateral sclerosis

The expression of glial cell line-derived neurotrophic factor (GDNF) mRNA and brain-derived neurotrophic factor (BDNF) mRNA were studied in muscle biopsies from five patients with amyotrophic lateral sclerosis (ALS), six patients with other neuromuscular diseases and eight healthy control persons. All five patients with ALS had higher GDNF mRNA expressions in their biopsies than the healthy control group (almost a three fold increase). Among the other patients only one, who had a rapidly progressing toxic polyneuropathy, showed a GDNF mRNA expression above those of the controls. The BDNF mRNA expressions in the biopsies from the ALS patients were in the same range as those from the healthy controls, although the mean value of the ALS patients was higher. The only biopsy that showed a markedly higher BDNF mRNA expression was taken from one patient with progressive muscular atrophy. These results suggest that increased GDNF mRNA expression in muscle is an unspecific response to ongoing denervation and that this response is maintained in ALS, at least temporarily. If increased GDNF mRNA in muscle proves to be a constant finding in ALS the rationale for the use of GDNF as a therapeutic agent in ALS must be questioned.     

IGF-1 and BDNF promote chick bulbospinal neurite outgrowth in vitro

Injured neurons in the CNS do not experience significant functional regeneration and so spinal cord insult often results in permanently compromised locomotor ability. The capability of a severed axon to re-grow is thought to depend on numerous factors, one of which is the decreased availability of neurotrophic factors. Application of trophic factors to axotomized neurons has been shown to enhance survival and neurite outgrowth. Although brainstem-spinal connections play a pivotal role in motor dysfunction after spinal cord injury, relatively little is known about the trophic sensitivity of these populations. This study explores the response of bulbospinal populations to various trophic factors. Several growth factors were initially examined for potential trophic effects on the projection neurons of the brainstem. Brain derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1) significantly enhance mean process length in both the vestibulospinal neurons and spinal projection neurons from the raphe nuclei. Nerve growth factor (NGF), neurotrophin-4 (NT-4) and glial derived neurotrophic factor (GDNF) did not effect process outgrowth in vestibulospinal neurons. At the developmental stages used in this study, it was determined that receptors for BDNF and IGF-1 were present both on bulbospinal neurons and on surrounding cells with a non-neuronal morphology.     

骨髓间充质干细胞静脉移植治疗大鼠脑梗死的机制研究

目的 观察炎性因子和营养因子在静脉植入同种异体骨髓间充质干细胞(MSC)治疗大鼠脑梗死中的作用.方法 采用大脑中动脉远端阻塞法(dMCAO)制作大鼠脑梗死模型,假手术组开颅但不凝断血管、移植组于造模后1h经尾静脉移植1×106大鼠骨髓MSC,缺血对照组注射等量生理盐水.移植后48 h取脑用ELISA法检测皮层梗死核心区及纹状体促炎因子TNF-α、IL-1β、IFN-γ、IL-6,抗炎因子IL-4、IL-10,以及营养因子IGF-1、GDNF、BDNF的含量.结果 同种异体骨髓MSC移植后48 h,和缺血对照组比较,移植组脑梗死区炎性因子IFN-γ、IL-6显著降低,TNF-α、IL-1β显著升高,纹状体区IL-10显著下降.移植组梗死区BDNF的含量比缺血对照组显著增高,纹状体区IGF-1的含量也比缺血对照组显著升高;GDNF在各组间无显著差异.结论 脑梗死后1h同种异体静脉移植骨髓MSC治疗dMCAO模型,其梗死后48 h时间点的治疗效果和MSC抑制炎性反应没有明确联系,而更可能和大鼠脑内营养性细胞因子增加有关.     

Changing responsiveness of developing midbrain dopaminergic neurons for extracellular growth factors

Numerous purified growth factors as well as yet-unidentified neurotrophic activities within mesencephalic glia support the survival of dopaminergic neurons. To further characterize the functional role of these multiple growth factor influences in dopaminergic cell development, various purified growth factors as well as mesencephalic glial-conditioned medium (CM) were screened for effects on dopaminergic cell survival and glial numbers in serum-free low density cultures of the dissociated embryonic day (E) 15 and E17 rat mesencephalon. In E15 mesencephalic cultures, dopaminergic cell survival increased with brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF), transforming growth factor α (TGFα), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-BB (PDGF-BB), and interleukin-6 (IL-6). bFGF, TGFα, PDGF, and IL-6 also stimulated glial proliferation as demonstrated by autoradiographic labeling for ³H-thymidine. Moreover, CM derived from the mesencephalic glial cell line Mes42 completely prevented the death of E15 dopaminergic neurons within the initial days of cultivation. In E17 mesencephalic cultures, survival-promoting effects on dopaminergic neurons were present with BDNF, GDNF, and bFGF. TGFα, IGF-1, PDGF-BB, and IL-6 stimulated glial proliferation but did not affect dopaminergic cell survival. Similarly, mesencephalic glial-CM completely failed to support the survival of E17 dopaminergic neurons. These observations demonstrate that during embryonic development, dopaminergic cell survival sequentially depends on distinct sets of growth factors. The concomitant loss of sensitivity of developing dopaminergic neurons for mesencephalic glial-CM as well as TGFα, IGF-1, PDGF-BB, and IL-6 further provides evidence that these growth factors indirectly affect early dopaminergic neurons through glial-mediated processes and suggests a crucial role of glia during the initial stages of neuronal development. J. Neurosci. Res. 51:508–516, 1998. © 1998 Wiley-Liss, Inc.     

Growth responses of different subpopulations of adult sensory neurons to neurotrophic factors in vitro

Different subpopulations of adult primary sensory neurons in the dorsal root ganglia express receptors for different trophic factors, and are therefore potentially responsive to distinct trophic signals. We have compared the effect of the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and NT-3, and of glial cell line-derived neurotrophic factor (GDNF) on neurite outgrowth in dissociated cultures of sensory neurons from the lumbar ganglia of young adult rats, and attempted to establish subset-specific effects of these trophic factors. We analysed three parameters of neurite growth (percentage of process-bearing neurons, length of longest neurite and total neurite length), which may correlate with particular types of axon growth in vivo, and may therefore respond differently to trophic factor presence. Our results showed that percentage of process-bearing neurons and total neurite length were influenced by trophic factors, whilst the length of the longest neurite was trophic factor independent. Only NGF and GDNF were found to enhance significantly the proportion of process-bearing neurons in vitro. GDNF was more effective than NGF on small, IB4- neurons, which are known to develop GDNF responsiveness early in postnatal development. NGF, and to a much lesser extent GDNF, enhanced the total length of the neurites produced by neurons in culture. BDNF exerted an inhibitory effect on growth, and both BDNF and NT-3 could partially block some of the growth-promoting effects of NGF on specific neuronal subpopulations.     

Down regulation of trophic factors in neonatal rat spinal cord after administration of cerebrospinal fluid from sporadic amyotrophic lateral sclerosis patients

Accumulating evidence supports neuroprotective role of trophic factors in amyotrophic lateral sclerosis (ALS). Previous studies from our laboratory report that the CSF of patients with sporadic ALS (ALS-CSF) induces degenerative changes in the rat spinal motor neurons and reactive astrogliosis in the surrounding gray matter. The present study was aimed to investigate if the ALS-CSF affected the expression of trophic factors namely, brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2) and insulin-like growth factor 1 (IGF1) in the newborn rat spinal cords. ALS-CSF was intrathecally injected into the neonatal rats and the mRNA levels of the trophic factors were determined by quantitative real-time polymerase chain reaction. Here, we report significant down regulation in the gene expression of trophic factors for BDNF, FGF2 and IGF1. BDNF mRNA levels were found to be reduced by 6.8-fold in the ALS-CSF injected group compared to control groups. The levels of IGF1 and FGF2 mRNA were also decreased by 3.91- and 2.13-fold, respectively, in the ALS group. We further found that exogenous supplementation of BDNF considerably reduced the aberrant phosphorylation of neurofilaments, complementing our earlier findings of restored expression of voltage gated sodium channel. Reduced expression of trophic factors indicates an altered microenvironment of the motor neurons and could possibly be one of the contributing factors in the degeneration process.     

Bone mesenchymal stromal cells stimulate neurite outgrowth of spinal neurons by secreting neurotrophic factors

It has been demonstrated that bone mesenchymal stromal cells (BMSCs) stimulate neurite outgrowth from dorsal root ganglion (DRG) neurons. The present in vitro study tested the hypothesis that BMSCs stimulate the neurite outgrowth from spinal neurons by secreting neurotrophic factors. Spinal neurons were cocultured with BMSCs, fibroblasts and control medium in a non-contact system. Neurite outgrowth of spinal neurons cocultured with BMSCs was significantly greater than the neurite outgrowth observed in neurons cultured with control medium or with fibroblasts. In addition, BMSC-conditioned medium increased the length of neurites from spinal neurons compared to those of neurons cultured in the control medium or in the fibroblasts-conditioned medium. BMSCs expressed brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). The concentrations of BDNF and GDNF in BMSC-conditioned medium were 132±12 and 70±6 pg ml(-1), respectively. The addition of anti-BDNF and anti-GDNF antibodies to BMSC-conditioned medium partially blocked the neurite-promoting effect of the BMSC-conditioned medium. In conclusion, our results demonstrate that BMSCs promote neurite outgrowth in spinal neurons by secreting soluble factors. The neurite-promoting effect of BMSCs is partially mediated by BDNF and GDNF.     

Mécanismes de dérégulation de la réponse à l’hypoxie dans la sclérose latérale amyotrophique

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motorneurons, leading to death in 3 to 5 years. Respiratory insufficiency and hypoxemia are closely linked during the clinical course of ALS. Chronic respiratory insufficiency and hypoxemia generally occur late in the disease course but rapid episodes of intermittent hypoxemia followed by reoxygenation can occur early and insidiously. Two pathways are involved in the response to hypoxemia: (i) hypoxia inducible factor-1 (HIF-1) and VEGF/HIF-2 and an erythropoietin (EPO) mediated pathway, in response to prolonged hypoxemia; and (ii) nuclear factor κ-B (NFκ-B) during acute hypoxemia followed by reoxygenation episodes, inducing inflammatory mediators: interleukin-6 (IL-6), TNF-α, cyclo oxygenase-2 (COX-2) and prostaglandin E-2 (PGE-2). Our aim was to specify the role of the different functional pathways of response to hypoxemia in sporadic ALS patients, compared with neurological controls and according to the level of hypoxemia. We report the results of several studies of hypoxemic and/or inflammatory mediators in the cerebrospinal fluid (CSF) from ALS patients, according to their respiratory status, showing a selective defect of HIF-1 mediated angiogenic factors (VEGF and angiogenin [ANG]) during chronic hypoxia in sporadic ALS patients, compared to hypoxemic neurological controls; contrasting with an early activation of the NFκ-B pathway since the isolated desaturation stage (IL-6, TNF-α, PGE-2, angiopoietin-2) in the same cohort of sporadic ALS patients. All these results are consistent with a selective impairment of the HIF-1 pathway during chronic hypoxemia in ALS patients. Inflammatory mediators were strongly elevated, since the early stage of the disease until chronic hypoxemia, suggesting a compensatory mechanism.     

Intrathecal injection of GDNF and BDNF induces immediate early gene expression in rat spinal dorsal horn

Glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) are potent trophic factors for dorsal root ganglion cells. In addition, these factors are produced in subsets of dorsal root ganglion cells and transported anterogradely to their terminals in the superficial dorsal horn of the spinal cord, where they constitute the only source of GDNF and BDNF. We investigated the effect of 10 mug GDNF and BDNF injected by lumbar puncture on the expression of the immediate early gene (IEG) products c-Fos, c-Jun, and Krox-24 in the adult rat dorsal horn. In the dorsal horn of S1 spinal segments, GDNF and BDNF induced a strong increase in IEG expression, which was most pronounced in laminae I and II (2.9- to 4.5-fold). More distal from the injection site, in the dorsal horn of L1/L2 spinal segments, the increase in IEG expression was less pronounced, suggesting a concentration-dependent effect. In order to explain the effects of intrathecally injected GDNF, we investigated whether lumbo-sacral dorsal horn neurons expressed RET protein, the signal-transducing element of the receptor complex for GDNF. It was found that several of these neurons contained RET immunoreactivity and that some of the RET-labeled neurons had the appearance of nociceptive-specific cells, confirming their presumed role in pain transmission. Additionally, using double-labeling immunofluorescence combined with confocal microscopy, it was found that after intrathecal GDNF injection 35% of c-Fos-labeled cells were also labeled for RET. These results demonstrate that intrathecally administered GDNF and BDNF induce IEG expression in dorsal horn neurons in the adult rat, supposedly by way of their cognate receptors, which are present on these neurons. We further suggest that the endogenous release of GDNF and BDNF, triggered by nociceptive stimuli, is involved in the induction of changes in spinal nociceptive transmission as in various pain states.     

Bone mesenchymal stromal cells stimulate neurite outgrowth of spinal neurons by secreting neurotrophic factors

Abstract

It has been demonstrated that bone mesenchymal stromal cells (BMSCs) stimulate neurite outgrowth from dorsal root ganglion (DRG) neurons. The present in vitro study tested the hypothesis that BMSCs stimulate the neurite outgrowth from spinal neurons by secreting neurotrophic factors. Spinal neurons were cocultured with BMSCs, fibroblasts and control medium in a non-contact system. Neurite outgrowth of spinal neurons cocultured with BMSCs was significantly greater than the neurite outgrowth observed in neurons cultured with control medium or with fibroblasts. In addition, BMSC-conditioned medium increased the length of neurites from spinal neurons compared to those of neurons cultured in the control medium or in the fibroblasts-conditioned medium. BMSCs expressed brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). The concentrations of BDNF and GDNF in BMSC-conditioned medium were 132±12 and 70±6 pg ml^?1, respectively. The addition of anti-BDNF and anti-GDNF antibodies to BMSC-conditioned medium partially blocked the neurite-promoting effect of the BMSC-conditioned medium. In conclusion, our results demonstrate that BMSCs promote neurite outgrowth in spinal neurons by secreting soluble factors. The neurite-promoting effect of BMSCs is partially mediated by BDNF and GDNF.     

GDNF is a major component of trophic activity in DA-depleted striatum for survival and neurite extension of DAergic neurons

Extracts from dopamine (DA)-depleted striatal tissue (lesion extract) and from intact striatal tissue (intact extract) were prepared, and trophic activities in these extracts were evaluated using survival and neurite extension of DAergic neurons as indices. Levels of brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF), glial cell-line derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) in extracts were measured using enzyme-linked immunosorbent assay (ELISA). The lesion extract exhibited a stronger trophic activity on survival and neurite extension of DAergic neurons than intact extract. In lesion extract, bFGF was slightly and GDNF was significantly increased, while BDNF and NT-3 were the same level in each extract. The peak increase of bFGF and GDNF was during 2 to 3 weeks after DA depletion. Trophic activity of extract was strongly attenuated after immunoprecipitation of GDNF and partly attenuated after immunoprecipitation of bFGF. In parallel immunohistological study, no significant variations were found for striatal microtubule-associated protein-2 (MAP-2)- nor OX-41-immunoreactive cells, while the number of strongly labeled glial fibrillary acidic protein (GFAP)-immunoreactive cells were increased in DA-depleted striatum, suggesting reactive gliosis. Data suggest that bFGF is a minor, while GDNF is a major component of trophic activity for DAergic neurons in DA-depleted striatum, and increased bFGF and GDNF levels may be mediated partly by reactive gliosis.     

Growth factors in combination, but not individually, rescue rd mouse photoreceptors in organ culture

The rd mouse retina is an animal model for human retinal dystrophy in which the rod photoreceptors undergo apoptosis during the first 4 weeks in vivo or in organ culture. We have examined the effect of different families of trophic factors on the survival of rd mouse photoreceptors in organ culture. Retinas were harvested from rd mice at postnatal day 2 and grown in organ culture for 27 days in vitro (DIV) in DMEM with 10% fetal calf serum. Ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), fibroblast growth factor-2 (FGF2), glial cell line-derived neurotrophic factor (GDNF), neurturin, and persephon were added individually or in combination to the medium at a dose of 50 ng/ml or less. CNTF + BDNF in combination resulted in photoreceptor survival comparable to wild-type retinas after 27 DIV. CNTF + FGF2 or CNTF + GDNF produced a partial prevention of photoreceptor death. Photoreceptor degeneration was not blocked by any of the trophic factors added individually. A significant increase in photoreceptor survival was seen with forskolin added to CNTF, but not to BDNF, FGF2, or GDNF. These results demonstrate that trophic factors promote photoreceptor survival through a synergistic interaction. Increased understanding of receptor interactions and signaling pathways may lead to a potential therapeutic role for combinatorial trophic factors in treatment of photoreceptor dystrophies.     

Altered serum levels of vascular endothelial growth factor and glial-derived neurotrophic factor but not fibroblast growth factor-2 in treatment-naive children with attention deficit/hyperactivity disorder

Abstract

Background and aim: Recent evidence suggests that growth factors might be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The aim of this study was to determine whether serum levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF), fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) were altered in children with ADHD.

Methods: Serum levels of BDNF, GDNF, NT-3, NGF, VEGF and FGF-2 were analyzed in 49 treatment- naive children with ADHD and age, gender matched 36 healthy controls using enzyme-linked immunosorbent assay. ADHD symptoms were scored by Du Paul ADHD Rating Scale and Strengths and Difficulties Questionnaire.

Results: We found that serum VEGF levels were significantly lower (p?<?0.001) and GDNF levels were significantly higher in ADHD group compared to control group (p?=?0.003). However, we found no correlations between ADHD symptoms and serum VEGF or GDNF levels. Furthermore, we observed no significant alterations in serum BDNF, NT-3, NGF, FGF-2 levels in children with ADHD.

Conclusion: To our knowledge, the present study is the first to examine serum VEGF and FGF-2 levels in children with ADHD. Our results indicate that VEGF and GDNF might be involved in the etiology of ADHD. Further studies are required to determine the role of growth factors in the etiology and consequently in the treatment of ADHD.     

A novel candidate region for ALS on chromosome 14q11.2

Sequence variations with biologic effect in ALS have been identified in the gene for vascular endothelial growth factor (VEGF). The gene for a related protein, angiogenin, lies on chromosome 14q11.2. Analysis of the angiogenin (ANG) gene in the authors' population has demonstrated a significant allelic association with the rs11701 single nucleotide polymorphism (SNP) and identified a novel mutation in two individuals with sporadic ALS that potentially inhibits angiogenin function. These observations propose a candidate region for ALS on chromosome 14q11.2 and suggest that other genes with similar function to VEGF may be important in the pathogenesis of ALS.     

Striatal trophic factor activity in aging monkeys with unilateral MPTP-induced parkinsonism

Striatal trophic activity was assessed in female rhesus monkeys of advancing age rendered hemiparkinsonian by unilateral intracarotid administration of MPTP. Three age groups were analyzed: young adults (8-9.5 years) n=4, middle-aged adults (15-17 years) n=4, and aged adults (21-31 years) n=7. Fresh frozen tissue punches of caudate nucleus and putamen were collected 3 months after MPTP treatment and assayed for combined soluble striatal trophic activity, brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). This time point was chosen in an effort to assess a relatively stable phase of the dopamine (DA)-depleted state that may model the condition of Parkinson's disease (PD) patients at the time of therapeutic intervention. Analyses were conducted on striatal tissue both contralateral (aging effects) and ipsilateral to the DA-depleting lesion (lesion x aging effects). We found that combined striatal trophic activity in the contralateral hemisphere increased significantly with aging. Activity from both middle-aged and aged animals was significantly elevated as compared to young adults. Following DA depletion, young animals significantly increased combined striatal trophic activity, but middle-aged and aged animals did not exhibit further increases in activity over their elevated baselines. BDNF levels in the contralateral hemisphere were significantly reduced in aged animals as compared to young and middle-aged subjects. With DA depletion, BDNF levels declined in young and middle-aged animals but did not change from the decreased baseline level in old animals. GDNF levels were unchanged with aging and at 3 months after DA depletion. The results are consistent with several conclusions. First, by middle age combined striatal trophic activity is elevated, potentially reflecting a compensatory reaction to ongoing degenerative changes in substantia nigra DA neurons. Second, in response to DA depletion, young animals were capable of generating a significant increase in trophic activity that was sustained for at least 3 months. This capacity was either saturated or was not sustained in middle-aged and aged animals. Third, the aging-related chronic increase in combined striatal trophic activity was not attributable to BDNF or GDNF as these molecules either decreased or did not change with aging.     

Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: growth factor production

Treatment of traumatic brain injury (TBI) with bone marrow stromal cells (MSCs) improves functional outcome in the rat. However, the specific mechanisms by which introduced MSCs provide benefit remain to be elucidated. Currently, the ability of therapeutically transplanted MSCs to replace injured parenchymal CNS tissue appears limited at best. Tissue replacement, however, is not the only possible compensatory avenue in cell transplantation therapy. Various growth factors have been shown to mediate the repair and replacement of damaged tissue, so trophic support provided by transplanted MSCs may play a role in the treatment of damaged tissue. We therefore investigated the temporal profile of various growth factors, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF), within cultures of human MSCs (hMSCs) conditioned with cerebral tissue extract from TBI. hMSCs were cultured with TBI extracts of rat brain in vitro and quantitative sandwich enzyme-linked immunosorbent assays (ELISAs) were performed. TBI-conditioned hMSCs cultures demonstrated a time-dependent increase of BDNF, NGF, VEGF, and HGF, indicating a responsive production of these growth factors by the hMSCs. The ELISA data suggest that transplanted hMSCs may provide therapeutic benefit via a responsive secretion of an array of growth factors that can foster neuroprotection and angiogenesis.