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Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which there is a progressive loss of motor neurons and their connections to muscle, leading to paralysis. In order to maintain muscle connections in a rat model of familial ALS (FALS), we performed intramuscular transplantation with human mesenchymal stem cells (hMSCs) used as "Trojan horses" to deliver growth factors to the terminals of motor neurons and to the skeletal muscles. hMSCs engineered to secrete glial cell line-derived neurotrophic factor (hMSC-GDNF) were transplanted bilaterally into three muscle groups. The cells survived within the muscle, released GDNF, and significantly increased the number of neuromuscular connections and motor neuron cell bodies in the spinal cord at mid-stages of the disease. Further, intramuscular transplantation with hMSC-GDNF was found to ameliorate motor neuron loss within the spinal cord where it connects with the limb muscles receiving transplants. While disease onset was similar in all the animals, hMSC-GDNF significantly delayed disease progression, increasing overall lifespan by up to 28 days, which is one of the largest effects on survival noted for this rat model of FALS. This preclinical data provides a novel and practical approach toward ex vivo gene therapy for ALS.

SUBMITTER: Suzuki M

PROVIDER: S-EPMC2678899 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS.

Suzuki Masatoshi M McHugh Jacalyn J Tork Craig C Shelley Brandon B Hayes Antonio A Bellantuono Ilaria I Aebischer Patrick P Svendsen Clive N CN

Molecular therapy : the journal of the American Society of Gene Therapy 20080916 12

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which there is a progressive loss of motor neurons and their connections to muscle, leading to paralysis. In order to maintain muscle connections in a rat model of familial ALS (FALS), we performed intramuscular transplantation with human mesenchymal stem cells (hMSCs) used as "Trojan horses" to deliver growth factors to the terminals of motor neurons and to the skeletal muscles. hMSCs engineered to secrete glial cell li ...[more]

PMID: 18797452

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Project description:BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by rapid loss of muscle control and eventual paralysis due to the death of large motor neurons in the brain and spinal cord. Growth factors such as glial cell line derived neurotrophic factor (GDNF) are known to protect motor neurons from damage in a range of models. However, penetrance through the blood brain barrier and delivery to the spinal cord remains a serious challenge. Although there may be a primary dysfunction in the motor neuron itself, there is also increasing evidence that excitotoxicity due to glial dysfunction plays a crucial role in disease progression. Clearly it would be of great interest if wild type glial cells could ameliorate motor neuron loss in these models, perhaps in combination with the release of growth factors such as GDNF.Methodology/principal findingsHuman neural progenitor cells can be expanded in culture for long periods and survive transplantation into the adult rodent central nervous system, in some cases making large numbers of GFAP positive astrocytes. They can also be genetically modified to release GDNF (hNPC(GDNF)) and thus act as long-term 'mini pumps' in specific regions of the rodent and primate brain. In the current study we genetically modified human neural stem cells to release GDNF and transplanted them into the spinal cord of rats over-expressing mutant SOD1 (SOD1(G93A)). Following unilateral transplantation into the spinal cord of SOD1(G93A) rats there was robust cellular migration into degenerating areas, efficient delivery of GDNF and remarkable preservation of motor neurons at early and end stages of the disease within chimeric regions. The progenitors retained immature markers, and those not secreting GDNF had no effect on motor neuron survival. Interestingly, this robust motor neuron survival was not accompanied by continued innervation of muscle end plates and thus resulted in no improvement in ipsilateral limb use.Conclusions/significanceThe potential to maintain dying motor neurons by delivering GDNF using neural progenitor cells represents a novel and powerful treatment strategy for ALS. While this approach represents a unique way to prevent motor neuron loss, our data also suggest that additional strategies may also be required for maintenance of neuromuscular connections and full functional recovery. However, simply maintaining motor neurons in patients would be the first step of a therapeutic advance for this devastating and incurable disease, while future strategies focus on the maintenance of the neuromuscular junction.

Project description:Transcriptional programming of cell identity promises to open up new frontiers in regenerative medicine by enabling the efficient production of clinically relevant cell types. We examine if such cellular programming is accomplished by transcription factors that each have an independent and additive effect on cellular identity, or if programming factors synergize to produce an effect that is not independently obtainable. The combinations of Ngn2-Isl1-Lhx3 and Ngn2-Isl1-Phox2a transcription factors program embryonic stem cells to express a spinal or cranial motor neuron identity respectively. The two alternate expression programs are determined by recruitment of Isl1/Lhx3 and Isl1/Phox2a pairs to distinct genomic locations characterized by two alternative dimeric homeobox motifs. These results suggest that the function of programming modules relies on synergistic interactions among transcription factors and thus cannot be extrapolated from the study of individual transcription factors in a different cellular context. In this study, we functionally characterize induced motor neurons that have been directly generated from ES cells via the forced expression of two different combinations of three transcription factors. Spinal motor neurons are induced via the expression of Ngn2, Isl1, and Lhx3 (iNIL), while cortical motor neurons are induced via the expression of Ngn2, Isl1, and Phox2a (iNIP). Here we profile the gene expression patterns of both types of induced motor neurons, directed differentiation motor neurons, and control cells. In all, 20 microarray experiments are provided in this submission, including 3 replicates of a control condition, 3 replicates of cells that have 24hrs induction of iNIL, 2 replicates of induced spinal motor neurons (induction of iNIL for 48hrs) that have been Hb9-GFP sorted, 3 replicates of induced spinal motor neurons exposed to retinoic acid that have been Hb9-GFP sorted, 3 replicates of motor neurons that have been differentiated in vitro using RA and Hh signalling, 3 replicates of induced cortical motor neurons (induction of iNIP for 48hrs), and 3 replicates of cells in which Isl1 in induced alone (induction of iI for 48hrs). For ChIP-Seq Samples: In this study, we functionally characterize induced motor neurons that have been directly generated from ES cells via the forced expression of two different combinations of three transcription factors. Spinal motor neurons are induced via the expression of Ngn2, Isl1, and Lhx3 (iNIL), while cortical motor neurons are induced via the expression of Ngn2, Isl1, and Phox2a (iNIP). The genome-wide binding of some of the programming factors is characterized here using ChIP-seq. We characterize the binding of Lhx3 and Isl1/2 in iNIL cells, Phox2a and Isl1/2 in iNIP cells, and Isl1/2 in cells in which Isl1 is induced alone (iI). There are 7 Illumina sequence datasets in this submission; one replicate for each of iLhx3-V5 and Isl1/2 in iNIL cells, two replicates for each of iPhox2a-V5 and Isl1/2 in iNIP cells, and one replicate for Isl1/2 in iI cells. An appropriate pseudo-IP control experiment is included.

Dataset Information

Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS.

Publications

Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS.

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