title: Human neural progenitors differentiate into astrocytes and protect motor neurons in aging rats.
abstract: Age-associated health decline presents a significant challenge to healthcare, although there are few animal models that can be used to test potential treatments. Here, we show that there is a significant reduction in both spinal cord motor neurons and motor function over time in the aging rat. One explanation for this motor neuron loss could be reduced support from surrounding aging astrocytes. Indeed, we have previously shown using in vitro models that aging rat astrocytes are less supportive to rat motor neuron function and survival over time. Here, we test whether rejuvenating the astrocyte niche can improve the survival of motor neurons in an aging spinal cord. We transplanted fetal-derived human neural progenitor cells (hNPCs) into the aging rat spinal cord and found that the cells survive and differentiate into astrocytes with a much higher efficiency than when transplanted into younger animals, suggesting that the aging environment stimulates astrocyte maturation. Importantly, the engrafted astrocytes were able to protect against motor neuron loss associated with aging, although this did not result in an increase in motor function based on behavioral assays. We also transplanted hNPCs genetically modified to secrete glial cell line-derived neurotrophic factor (GDNF) into the aging rat spinal cord, as this combination of cell and protein delivery can protect motor neurons in animal models of ALS. During aging, GDNF-expressing hNPCs protected motor neurons, though to the same extent as hNPCs alone, and again had no effect on motor function. We conclude that hNPCs can survive well in the aging spinal cord, protect motor neurons and mature faster into astrocytes when compared to transplantation into the young spinal cord. While there was no functional improvement, there were no functional deficits either, further supporting a good safety profile of hNPC transplantation even into the older patient population.
authors.affiliation: The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Das
authors.affiliation: The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
authors.forename: Pablo
authors.initials: P
authors.lastname: Avalos
authors.affiliation: The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Suezaki
authors.affiliation: The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
authors.forename: Marlesa
authors.initials: M
authors.lastname: Godoy
authors.affiliation: The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
authors.forename: Leslie
authors.initials: L
authors.lastname: Garcia
authors.affiliation: The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
authors.forename: Christine D
authors.initials: CD
authors.lastname: Chang
authors.affiliation: Biobehavioral Research Core, Cedars-Sinai Medical Center, Los Angeles, CA, United States; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Vit
authors.affiliation: The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
authors.forename: Brandon
authors.initials: B
authors.lastname: Shelley
authors.affiliation: The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Gowing
authors.affiliation: The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
authors.forename: Clive N
authors.initials: CN
authors.lastname: Svendsen
mesh_terms: D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D001835:Body Weight / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005333:Fetus / Q000166:cytology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009046:Motor Neurons / Q000502:physiology*; D009069:Movement Disorders / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D053580:Muscle Strength / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology* / Q000637:transplantation; D009469:Neuromuscular Junction / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000637:transplantation
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins
keywords: Aging; Astrocytes; Glial cell line-derived neurotrophic factor; Motor neuron; Neural progenitors; Transplantation