Transplantation of Human Adipose Tissue-Derived Stem Cells Delays Clinical Onset and Prolongs Life Span in ALS Mouse Model

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects motor neurons in the cortex, brain stem, and spinal cord. The precise pathogenic mechanism remains unknown, and there is currently no effective therapy. We evaluated the therapeutic effects of human adipose tissue-derived stem cells (ASCs) in an animal model of ALS. Human abdominal subcutaneous fat tissues were obtained by simple liposuction from donors, and ASCs were isolated from the fat stromal vascular fraction. ASCs were found to differentiate into adipocytes, chondrocytes, osteocytes, and neurons. SOD1G93A ALS mice were divided into three groups: sham, intravenous (IV), and intracerebroventricular (ICV) groups. Human ASCs were transplanted in the ALS mice at 70 postnatal days before the appearance of clinical symptoms. Behavior of transplanted animals was assessed by rotarod test, paw grip endurance (PaGE), and reflex index. Mice in every group were sacrificed after 4 weeks posttransplantation. Transplanted ASCs were identified in the lumbar spinal cords with an antihuman mitochondria antibody and cell type-specific markers for neurons or astrocytes. Delayed onset of clinical symptoms (26 days) and extended survival of animals (24 days) were observed in ALS mice transplanted with ASCs via ICV route. ASCs were found to secrete high levels of neurotrophic factors such as NGF, BDNF, IGF-1, and VEGF. Reduction of apoptotic cell death by these factors was confirmed in cultured CNS cells and in the ALS spinal cord. These results indicate that transplantation of ASCs in ALS mice provides neuroprotective effects by production of cytokines/growth factors, delays disease progression, and prolongs the life span of ALS mice.

Adipose stem cells’ antagonism in glycosylation of D-galactose-induced skin aging of nude mice and its skin recovery function

“…A large number of evidences indicated that ASCs could accelerate angiogenesis of tissues through secreting VEGF and hepatocyte growth factors. 23,24 Results in this study verified that ASCs could induce angiogenesis of skin tissues through secreting VEGF, and CD31 immunohistochemical staining further verified that ASCs could provide nutrients for skin tissues. Although some research verified that ASCs could differentiate into vascular endothelial cells and thus provide skin tissues with more nutrients, considering ASCs almost disappeared on day 28 after transplantation, we hold the opinion that ASCs mainly participated in repairing tissue damage and accelerating angiogenesis through paracrine mechanism.…”

Therapeutic Potential of Human Adipose-Derived Stem Cells in Neurological Disorders

“…In Tg mice transplanted with ASCs via the i.c.v. route, delayed clinical symptoms were shown by behavior assessments such as the rotarod test, paw grip endurance, and reflex index; and the survival of animals was extended (24). In cultured neuronal cells and in the ALS spinal cord, ASCs secreted high levels of neurotrophic factors such as nerve growth factor (NGF), brainderived neurotropic factor (BDNF), insulin-like growth factor 1 (IGF-1), and VEGF and reduced the cytotoxicity by these factors (24).…”

“…and intracerebroventricularly (i.c.v.) transplanted into Tg mice before the appearance of clinical symptoms (24). In Tg mice transplanted with ASCs via the i.c.v.…”

“…A recent study from Kim et al suggest that transplantation of ASCs in [SOD1-G93A] Tg mice delays disease progression and prolongs life span of Tg mice through neuroprotective effects by production of cytokines/ growth factors (24). Human ASCs were intravenously (i.v.)…”

Stem Cells for Neuro-regeneration: State of the Art

“…Neurodegenerative diseases: Amyotrophic lateral sclerosis (ALS) About 10% of ALS cases are familial (fALS), among which 15-20% is due to mutations in Cu/Zn superoxide dismutase (SOD1) [49]. Stem cells used in ALS may be directed towards regenerating damaged neurones or introduction of cells producing growth factors.…”