Minimally invasive transplantation of iPSC-derived ALDHhiSSCloVLA4+ neural stem cells effectively improves the phenotype of an amyotrophic lateral sclerosis model

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by the degeneration of motor neurons. Currently, there is no effective therapy for ALS. Stem cell transplantation is a potential therapeutic strategy for ALS, and the reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) represents a novel cell source. In this study, we isolated a specific neural stem cell (NSC) population from human iPSCs based on high aldehyde dehydrogenase activity, low side scatter and integrin VLA4 positivity. We assessed the therapeutic effects of these NSCs on the phenotype of ALS mice after intrathecal or intravenous injections. Transplanted NSCs migrated and engrafted into the central nervous system via both routes of injection. Compared with control ALS, treated ALS mice exhibited improved neuromuscular function and motor unit pathology and significantly increased life span, in particular with the systemic administration of NSCs (15%). These positive effects are linked to multiple mechanisms, including production of neurotrophic factors and reduction of micro- and macrogliosis. NSCs induced a decrease in astrocyte number through the activation of the vanilloid receptor TRPV1. We conclude that minimally invasive injections of iPSC-derived NSCs can exert a therapeutic effect in ALS. This study contributes to advancements in iPSC-mediated approaches for treating ALS and other neurodegenerative diseases.

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

“…This neuroprotection correlated with decreased inflammation, as shown by a decrease in the proliferation of microglial cells and reduced expression of inflammatory-related genes, COX-2 and NOX-2 [75] . Recent publications confirmed that transplantation of stem cells indeed reduces neuroinflammation and suggests that alleviating astrocytosis or microgliosis is an important parameter leading to both histological and functional improvement in ALS animal models [144,145] . Another approach was tested by Mitrecić et al [135] .…”

Stem Cell Therapy for Amyotrophic Lateral Sclerosis

“…In a series of longterm studies, Chen et al showed iPSC-derived neural progenitors mostly differentiated into astrocytes, replaced the endogenous astrocytes, formed networks through their processes, and encircled endogenous neurons [68]. Preclinical studies, currently being conducted at Johns Hopkins University, use human iPSC-derived glial-restricted precursors (iPSC-GRPs) [88] and may offer perspectives for the use of iPSC-based therapy in ALS [87].…”

Neural and glial progenitor transplantation as a neuroprotective strategy for Amyotrophic Lateral Sclerosis (ALS)

“…Alternatively, intrathecal injection of stem cells could allow for more targeted administration of stem cells into the CNS although penetration of the cells from the cerebrospinal fluid into the parenchyma may still be a significant hurdle to overcome. In a recent study, Nizzardo et al (2014) compared the delivery of human induced pluripotent stem cell-derived neural stem cells by either intrathecal or intravenous delivery in the SOD1 G93A mouse model of ALS. To enhance the homing potential of stem cells to enter the parenchyma after intravenous delivery, the authors used fluorescence activated cell sorting (FACS) to isolate a population of human induced pluripotent stem cell-derived neural stem cells expressing the VLA4 integrin allowing for enhanced binding to the blood-brain-barrier via adhesion molecules .…”

“…Human induced pluripotent stem cells are self-renewing, largely expandable, and can differentiate to endoderm, ectoderm, or mesoderm germ lineages. Indeed, recent reports show that human induced pluripotent stem cells differentiated to neural progenitor lineages can be engrafted to the spinal cord of the SOD1 mouse model of ALS with modest phenotypic improvement (Kondo et al, 2014;Nizzardo et al, 2014). In addition to the avoidance of ethical issues, human induced pluripotent stem cells offer another potential advantage for cell therapy since they can be reprogrammed directly from cells isolated from a patient biopsy.…”