Inner ear hair cell-like cells from human embryonic stem cells.
Stem cells and development
Concise Review: Inner Ear Stem Cells-An Oxymoron, but Why?
2012; 30 (1): 69-74
In mammals, the permanence of many forms of hearing loss is the result of the inner ear's inability to replace lost sensory hair cells. Here, we apply a differentiation strategy to human embryonic stem cells into cells of the otic lineage using chemically-defined attached-substrate conditions. Generation of human otic progenitor cells was dependent on FGF signaling and protracted culture led to the upregulation of markers indicative of differentiated inner ear sensory epithelia. Using a transgenic embryonic stem cell reporter line based on a murine Atoh1 enhancer, we show that differentiated hair cell-like cells express multiple hair cell markers simultaneously. Hair cell-like cells displayed protrusions reminiscent of stereociliary bundles, but failed to fully mature into cells with typical hair cell cytoarchitecture. We conclude that optimized defined conditions can be used in vitro to attain otic progenitor specification and sensory cell differentiation.
View details for DOI 10.1089/scd.2014.0033
View details for PubMedID 24512547
Challenges of Stem Cell Therapy for Spinal Cord Injury: Human Embryonic Stem Cells, Endogenous Neural Stem Cells, or Induced Pluripotent Stem Cells?
2010; 28 (1): 93-99
Hearing loss, caused by irreversible loss of cochlear sensory hair cells, affects millions of patients worldwide. In this concise review, we examine the conundrum of inner ear stem cells, which obviously are present in the inner ear sensory epithelia of nonmammalian vertebrates, giving these ears the ability to functionally recover even from repetitive ototoxic insults. Despite the inability of the mammalian inner ear to regenerate lost hair cells, there is evidence for cells with regenerative capacity because stem cells can be isolated from vestibular sensory epithelia and from the neonatal cochlea. Challenges and recent progress toward identification of the intrinsic and extrinsic signaling pathways that could be used to re-establish stemness in the mammalian organ of Corti are discussed.
View details for DOI 10.1002/stem.785
View details for Web of Science ID 000298598400012
View details for PubMedID 22102534
Human Embryonic Stem Cell Differentiation Toward Regional Specific Neural Precursors
2009; 27 (1): 78-87
Spinal cord injury (SCI) causes myelopathy, damage to white matter, and myelinated fiber tracts that carry sensation and motor signals to and from the brain. The gray matter damage causes segmental losses of interneurons and motoneurons and restricts therapeutic options. Recent advances in stem cell biology, neural injury, and repair, and the progress toward development of neuroprotective and regenerative interventions are the basis for increased optimism. This review summarizes the pathophysiological mechanisms following SCI and compares human embryonic, adult neural, and the induced pluripotent stem cell-based therapeutic strategies for SCI.
View details for DOI 10.1002/stem.253
View details for Web of Science ID 000274496600013
View details for PubMedID 19904738
Differentiation of Human Embryonic Stem Cells to Regional Specific Neural Precursors in Chemically Defined Medium Conditions
2008; 3 (5)
Human embryonic stem cells (hESCs) are self-renewing pluripotent cells that have the capacity to differentiate into a wide variety of cell types. This potentiality represents a promising source to overcome many human diseases by providing an unlimited supply of all cell types, including cells with neural characteristics. Therefore, this review summarizes early neural development and the potential of hESCs to differentiate under in vitro conditions, examining at the same time the potential use of differentiated hESCs for therapeutic applications for neural tissue and cell regeneration.
View details for DOI 10.1634/stemcells.2008-0543
View details for Web of Science ID 000263032400010
View details for PubMedID 18845761
Efficient Differentiation of Human Embryonic Stem Cells into Functional Cerebellar-Like Cells
STEM CELLS AND DEVELOPMENT
2010; 19 (11): 1745-1756
Human embryonic stem cells (hESC) provide a unique model to study early events in human development. The hESC-derived cells can potentially be used to replace or restore different tissues including neuronal that have been damaged by disease or injury.The cells of two different hESC lines were converted to neural rosettes using adherent and chemically defined conditions. The progenitor cells were exposed to retinoic acid (RA) or to human recombinant basic fibroblast growth factor (bFGF) in the late phase of the rosette formation. Exposing the progenitor cells to RA suppressed differentiation to rostral forebrain dopamine neural lineage and promoted that of spinal neural tissue including motor neurons. The functional characteristics of these differentiated neuronal precursors under both, rostral (bFGF) and caudalizing (RA) signals were confirmed by patch clamp analysis.These findings suggest that our differentiation protocol has the capacity to generate region-specific and electrophysiologically active neurons under in vitro conditions without embryoid body formation, co-culture with stromal cells and without presence of cells of mesodermal or endodermal lineages.
View details for DOI 10.1371/journal.pone.0002122
View details for Web of Science ID 000261642400043
View details for PubMedID 18461168
Transplanted Oligodendrocytes and Motoneuron Progenitors Generated from Human Embryonic Stem Cells Promote Locomotor Recovery After Spinal Cord Transection
2010; 28 (9): 1541-1549
The cerebellum has critical roles in motor and sensory learning and motor coordination. Many cerebellum-related disorders indicate cell therapy as a possible treatment of neural loss. Here we show that application of inductive signals involved in early patterning of the cerebellar region followed by application of different factors directs human embryonic stem cell differentiation into cerebellar-like cells such as granule neurons, Purkinje cells, interneuron, and glial cells. Neurons derived using our protocol showed a T-shaped polarity phenotype and express similar markers to the developed human cerebellum. Electrophysiological measurements confirmed functional electrical properties compatible with these cells. In vivo implantation of differentiated human embryonic stem cells transfected with MATH1-GFP construct into neonatal mice resulted in cell migration across the molecular and the Purkinje cell layers and settlement in the internal molecular layers. Our findings demonstrate that the universal mechanisms involved in the development of cerebellum can be efficiently recapitulated in vitro, which enables the design of new strategies for cell replacement therapy, to study early human development and pathogenesis of neurodegenerative diseases.
View details for DOI 10.1089/scd.2009.0498
View details for Web of Science ID 000283544200010
View details for PubMedID 20521974
CD24 gene polymorphism is associated with the disease progression and susceptibility to multiple sclerosis in the Iranian population
2009; 170 (2-3): 271-272
Human embryonic stem cells (hESC) hold great promise for the treatment of patients with many neurodegenerative diseases particularly those arising from cell loss or neural dysfunction including spinal cord injury. This study evaluates the therapeutic effects of transplanted hESC-derived oligodendrocyte progenitors (OPC) and/or motoneuron progenitors (MP) on axonal remyelination and functional recovery of adult rats after complete spinal cord transection. OPC and/or MP were grafted into the site of injury in the acute phase. Based on Basso-Beattie-Bresnahan scores recovery of locomotor function was significantly enhanced in rats treated with OPC and/or MP when compared with control animals. When transplanted into the spinal cord immediately after complete transection, OPC and MP survived, migrated, and differentiated into mature oligodendrocytes and neurons showing in vivo electrophysiological activity. Taken together, these results indicate that OPC and MP derived from hESC could be a useful therapeutic strategy to repair injured spinal cord.
View details for DOI 10.1002/stem.489
View details for Web of Science ID 000282454700010
View details for PubMedID 20665739
Activated Spinal Cord Ependymal Stem Cells Rescue Neurological Function
2009; 27 (3): 733-743
The impact of a single nucleotide polymorphism (SNP) in the CD24 gene on the risk and progression of multiple sclerosis (MS) was investigated in the Iranian population. Our data revealed that the susceptibility and the progression of MS in individuals with the CD24V/V genotype were greater than in those with the CD24A/V and CD24A/A genotypes.
View details for DOI 10.1016/j.psychres.2009.01.002
View details for Web of Science ID 000272855200032
View details for PubMedID 19896210
Spinal cord injury (SCI) is a major cause of paralysis. Currently, there are no effective therapies to reverse this disabling condition. The presence of ependymal stem/progenitor cells (epSPCs) in the adult spinal cord suggests that endogenous stem cell-associated mechanisms might be exploited to repair spinal cord lesions. epSPC cells that proliferate after SCI are recruited by the injured zone, and can be modulated by innate and adaptive immune responses. Here we demonstrate that when epSPCs are cultured from rats with a SCI (ependymal stem/progenitor cells injury [epSPCi]), these cells proliferate 10 times faster in vitro than epSPC derived from control animals and display enhanced self renewal. Genetic profile analysis revealed an important influence of inflammation on signaling pathways in epSPCi after injury, including the upregulation of Jak/Stat and mitogen activated protein kinase pathways. Although neurospheres derived from either epSPCs or epSPCi differentiated efficiently to oligodendrocites and functional spinal motoneurons, a better yield of differentiated cells was consistently obtained from epSPCi cultures. Acute transplantation of undifferentiated epSPCi or the resulting oligodendrocyte precursor cells into a rat model of severe spinal cord contusion produced a significant recovery of motor activity 1 week after injury. These transplanted cells migrated long distances from the rostral and caudal regions of the transplant to the neurofilament-labeled axons in and around the lesion zone. Our findings demonstrate that modulation of endogenous epSPCs represents a viable cell-based strategy for restoring neuronal dysfunction in patients with spinal cord damage.
View details for DOI 10.1002/stem.24
View details for Web of Science ID 000264706900024
View details for PubMedID 19259940