ORCID Profile
0000-0001-8321-0852
Current Organisations
Flinders University
,
SAHMRI
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Cellular nervous system | Proteins and Peptides | Neurogenetics | Characterisation of Biological Macromolecules | Medicinal and Biomolecular Chemistry | Neural engineering | Biologically Active Molecules | Neurosciences
Nervous System and Disorders | Expanding Knowledge in the Agricultural and Veterinary Sciences | Expanding Knowledge in the Biological Sciences |
Publisher: Springer Science and Business Media LLC
Date: 25-01-2012
DOI: 10.1038/NATURE10821
Publisher: Cold Spring Harbor Laboratory
Date: 03-09-2020
DOI: 10.1101/2020.09.02.276535
Abstract: The capabilities of imaging technologies, fluorescent sensors, and optogenetics tools for cell biology have improved exponentially in the last ten years. At the same time, advances in cellular reprogramming and organoid engineering have quickly expanded the use of human neuronal models in vitro . Altogether this creates an increasing need for tissue culture conditions better adapted to live-cell imaging. Here, we identified multiple caveats of traditional media when used for live imaging and functional assays on neuronal cultures (e.g., phototoxicity, suboptimal fluorescence signals, and unphysiological neuronal activity). To overcome these issues, we developed a new neuromedium, “BrainPhys™ Imaging”, in which we adjusted fluorescent and phototoxic compounds. The new medium is based on the formulation of the original BrainPhys medium, which we designed to better support the neuronal activity of human neurons in vitro 1 . We tested the new imaging-optimized formulation on human neurons cultured in monolayers or organoids, and rat primary neurons. BrainPhys Imaging enhanced fluorescence signals and reduced phototoxicity throughout the entire light spectrum. Importantly, consistent with standard BrainPhys, we showed that the new imaging medium optimally supports the electrical and synaptic activity of midbrain and human cortical neurons in culture. We also benchmarked the capacity of the new medium for functional calcium imaging and optogenetic control of human neurons. Altogether, our study shows that the new BrainPhys Imaging improves the quality of a wide range of fluorescence imaging applications with live neurons in vitro while supporting cell viability and neuronal functions.
Publisher: Elsevier
Date: 2020
Publisher: Future Medicine Ltd
Date: 08-2016
Abstract: Enforced ectopic expression of a cocktail of pluripotency-associated genes such as Oct4, Sox2, Klf4 and c-Myc can reprogram somatic cells into induced pluripotent stem cells (iPSCs). The remarkable proliferation ability of iPSCs and their aptitude to redifferentiate into any cell lineage makes these cells a promising tool for generating a variety of human tissue in vitro. Yet, pluripotency induction is an inefficient process, as cells undergoing reprogramming need to overcome developmentally imposed epigenetic barriers. Recent work has shed new light on the molecular mechanisms that drive the reprogramming of somatic cells to iPSCs. Here, we present current knowledge on the transcriptional and epigenetic regulation of pluripotency induction and discuss how variability in epigenetic states impacts iPSCs’ inherent biological properties.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.JNEUMETH.2019.108350
Abstract: Advances in human cell reprogramming and induced pluripotent stem cell technologies generate tremendous potential for neuroscience studies in health and disease, while the neuroscientist toolbox for engineering a range of brain tissues and neuronal cell types is rapidly expanding. Here, we discuss how the emergence of new single-cell genomics methods may help benchmarking and optimizing the tissue engineering process. The inherent heterogeneity and variability of reprogrammed brain tissue may conceal important disease mechanisms if not accounted for by rigorous experimental design. Single-cell genomics methods may address this technical challenge and ultimately improve the development of new therapeutics for neurological and psychiatric disorders.
Publisher: Informa UK Limited
Date: 22-09-2020
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1191
Publisher: Elsevier BV
Date: 03-2022
Publisher: Springer Science and Business Media LLC
Date: 04-10-2016
DOI: 10.1038/MP.2016.158
Publisher: Springer Science and Business Media LLC
Date: 10-08-2022
DOI: 10.1038/S41531-022-00366-Z
Abstract: Several mutations that cause Parkinson’s disease (PD) have been identified over the past decade. These account for 15–25% of PD cases the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology.
Publisher: Wiley
Date: 21-07-2006
Publisher: Springer Science and Business Media LLC
Date: 24-04-2020
DOI: 10.1038/S41531-020-0110-8
Abstract: Parkinson’s disease (PD) is the second most prevalent neurological disorder and has been the focus of intense investigations to understand its etiology and progression, but it still lacks a cure. Modeling diseases of the central nervous system in vitro with human induced pluripotent stem cells (hiPSC) is still in its infancy but has the potential to expedite the discovery and validation of new treatments. Here, we discuss the interplay between genetic predispositions and midbrain neuronal impairments in people living with PD. We first summarize the prevalence of causal Parkinson’s genes and risk factors reported in 74 epidemiological and genomic studies. We then present a meta-analysis of 385 hiPSC-derived neuronal lines from 67 recent independent original research articles, which point towards specific impairments in neurons from Parkinson’s patients, within the context of genetic predispositions. Despite the heterogeneous nature of the disease, current iPSC models reveal converging molecular pathways underlying neurodegeneration in a range of familial and sporadic forms of Parkinson’s disease. Altogether, consolidating our understanding of robust cellular phenotypes across genetic cohorts of Parkinson’s patients may guide future personalized drug screens in preclinical research.
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.BRAINRES.2010.02.069
Abstract: 'Feedback' signals from mammalian extrastriate visual cortices are reported to exert primarily an excitatory influence on the classical receptive field (CRF) of neurons in the primary visual cortex (V1). However, given the much larger CRFs of neurons in extrastriate visual cortices it is not yet understood how feedback signals influence the spatial integration of visual signals by V1 neurons. To investigate this, we reversibly inactivated one of the 'form-processing' extrastriate visual cortices, the postero-temporal visual (PTV) cortex, and examined changes in responses of V1 neurons to drifting grating patches up to 28 degrees in diameter. We found that during inactivation of PTV cortex the magnitude of the responses to CRF-confined stimuli and that to large stimuli inducing maximum suppression (i.e. minimum responses) was significantly reduced, while the spatial extent of the CRF remained largely unaffected. As a result, the relative strength of the surround suppression increased marginally. This effect was apparent in both simple and complex cells. It was also strong and consistent in cells located in supragranular and infragranular layers. For those cells exhibiting some relief from surround suppression or 'counter-suppression' when large stimuli patches were applied, the effect on counter-suppression was heterogeneous. Overall, the relative integrated responses to the 28 degrees grating patches were also decreased when PTV cortex was inactivated. Thus, a substantial reduction in the CRF response and the largely unaffected spatial extent of the CRF as well as a weak surround effect observed in the present study are consistent with a multiplicative scaling effect.
Publisher: Frontiers Media SA
Date: 10-08-2018
Publisher: Society for Neuroscience
Date: 15-12-2010
DOI: 10.1523/JNEUROSCI.4543-10.2010
Abstract: Adult-born neurons continuously incorporate into the olfactory bulb where they rapidly establish contacts with a variety of synaptic inputs. Little is known, however, about the functional properties of their output. Characterization of synaptic outputs from new neurons is essential to assess the functional impact of adult neurogenesis on mature circuits. Here, we used optogenetics to control neurotransmitter release from new neurons. We found that light-induced synaptic GABA release from adult-born neurons leads to profound modifications of postsynaptic target firing patterns. We revealed that functional output synapses form just after new cells acquire the faculty to spike, but most synapses were made a month later. Despite discrepancies in the timing of new synapse recruitment, the properties of postsynaptic signals remain constant. Remarkably, we found that all major cell types of the olfactory bulb circuit, including output neurons and several distinct subtypes of local interneurons, were contacted by adult-born neurons. Thus, this study provides new insights into how new neurons integrate into the adult neural network and may influence the sense of smell.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2016
DOI: 10.1038/NRN.2016.46
Publisher: Springer Science and Business Media LLC
Date: 27-10-2016
DOI: 10.1038/MP.2015.161
Abstract: The brain's serotonergic system centrally regulates several physiological processes and its dysfunction has been implicated in the pathophysiology of several neuropsychiatric disorders. While in the past our understanding of serotonergic neurotransmission has come mainly from mouse models, the development of pluripotent stem cell and induced fibroblast-to-neuron (iN) transdifferentiation technologies has revolutionized our ability to generate human neurons in vitro. Utilizing these techniques and a novel lentiviral reporter for serotonergic neurons, we identified and overexpressed key transcription factors to successfully generate human serotonergic neurons. We found that overexpressing the transcription factors NKX2.2, FEV, GATA2 and LMX1B in combination with ASCL1 and NGN2 directly and efficiently generated serotonergic neurons from human fibroblasts. Induced serotonergic neurons (iSNs) showed increased expression of specific serotonergic genes that are known to be expressed in raphe nuclei. iSNs displayed spontaneous action potentials, released serotonin in vitro and functionally responded to selective serotonin reuptake inhibitors (SSRIs). Here, we demonstrate the efficient generation of functional human serotonergic neurons from human fibroblasts as a novel tool for studying human serotonergic neurotransmission in health and disease.
Publisher: Society for Neuroscience
Date: 02-12-2009
DOI: 10.1523/JNEUROSCI.3034-09.2009
Abstract: New olfactory bulb granule cells (GCs) are GABAergic interneurons continuously arising from neuronal progenitors and integrating into preexisting bulbar circuits. They receive both GABAergic and glutamatergic synaptic inputs from olfactory bulb intrinsic neurons and centrifugal afferents. Here, we investigated the spatiotemporal dynamic of newborn GC synaptogenesis in adult mouse olfactory bulb. First, we established that GABAergic synapses onto mature GC dendrites contain the GABA A receptor α2 subunit along with the postsynaptic scaffolding protein gephyrin. Next, we characterized morphologically and electrophysiologically the development of GABAergic and glutamatergic inputs onto newborn GCs labeled with eGFP (enhanced green fluorescent protein) using lentiviral vectors. Already when reaching the GC layer (GCL), at 3 d post-vector injection (dpi), newborn GCs exhibited tiny voltage-dependent sodium currents and received functional GABAergic and glutamatergic synapses, recognized immunohistochemically by apposition of specific presynaptic and postsynaptic markers. Thereafter, GABAergic and glutamatergic synaptic contacts increased differentially in the GCL, and at 7 dpi, PSD-95 clusters outnumbered gephyrin clusters. Thus, the weight of GABAergic input was predominant at early stages of GC maturation, but not later. Newborn GC dendrites first reached the external plexiform layer at 4 dpi, where they received functional GABAergic contacts at 5 dpi. Reciprocal synapses initially were formed on GC dendritic shafts, where they might contribute to spine formation. Their presence was confirmed ultrastructurally at 7 dpi. Together, our findings unravel rapid synaptic integration of newborn GCs in adult mouse olfactory bulb, with GABAergic and glutamatergic influences being established proximally before formation of output synapses by apical GC dendrites onto mitral/tufted cells.
Publisher: Springer Science and Business Media LLC
Date: 03-05-2009
DOI: 10.1038/NN.2298
Abstract: To explore the functional consequences of adult neurogenesis in the mouse olfactory bulb, we investigated plasticity at glutamatergic synapses onto GABAergic interneurons. We found that one subset of excitatory synapses onto adult-born granule cells showed long-term potentiation shortly after their arrival in the bulb. This property faded as the newborn neurons matured. These results indicate that recently generated adult-born olfactory interneurons undergo different experience-dependent synaptic modifications compared with their pre-existing mature neighbors and provide a possible substrate for adult neurogenesis-dependent olfactory learning.
Publisher: Frontiers Media SA
Date: 24-02-2022
Publisher: Proceedings of the National Academy of Sciences
Date: 13-04-2015
Abstract: Neuronal cultures are very valuable to learn about basic principles of the nervous system. In vivo, neural electrical activity is the essence of nervous system function, controlling emotion, memory, sensory modalities, and behavior. In this study, we discovered that many crucial neurophysiological properties were strongly altered in classic culture media that are widely used by the research community. To overcome this problem, we designed and tested a new tissue culture neuromedium that adequately supports in vitro neuronal activity. The improvements made in this medium reduce the gap between in vivo brain physiological conditions and neuronal models in vitro. Improving physiological conditions in vitro may lead to more successful translation from bench to clinics.
Publisher: Springer Science and Business Media LLC
Date: 03-11-2020
DOI: 10.1038/S41467-020-19275-X
Abstract: The capabilities of imaging technologies, fluorescent sensors, and optogenetics tools for cell biology are advancing. In parallel, cellular reprogramming and organoid engineering are expanding the use of human neuronal models in vitro. This creates an increasing need for tissue culture conditions better adapted to live-cell imaging. Here, we identify multiple caveats of traditional media when used for live imaging and functional assays on neuronal cultures (i.e., suboptimal fluorescence signals, phototoxicity, and unphysiological neuronal activity). To overcome these issues, we develop a neuromedium called BrainPhys™ Imaging (BPI) in which we optimize the concentrations of fluorescent and phototoxic compounds. BPI is based on the formulation of the original BrainPhys medium. We benchmark available neuronal media and show that BPI enhances fluorescence signals, reduces phototoxicity and optimally supports the electrical and synaptic activity of neurons in culture. We also show the superior capacity of BPI for optogenetics and calcium imaging of human neurons. Altogether, our study shows that BPI improves the quality of a wide range of fluorescence imaging applications with live neurons in vitro while supporting optimal neuronal viability and function.
Publisher: eLife Sciences Publications, Ltd
Date: 23-03-2016
DOI: 10.7554/ELIFE.13378
Abstract: mTOR inhibition is beneficial in neurodegenerative disease models and its effects are often attributable to the modulation of autophagy and anti-apoptosis. Here, we report a neglected but important bioenergetic effect of mTOR inhibition in neurons. mTOR inhibition by rapamycin significantly preserves neuronal ATP levels, particularly when oxidative phosphorylation is impaired, such as in neurons treated with mitochondrial inhibitors, or in neurons derived from maternally inherited Leigh syndrome (MILS) patient iPS cells with ATP synthase deficiency. Rapamycin treatment significantly improves the resistance of MILS neurons to glutamate toxicity. Surprisingly, in mitochondrially defective neurons, but not neuroprogenitor cells, ribosomal S6 and S6 kinase phosphorylation increased over time, despite activation of AMPK, which is often linked to mTOR inhibition. A rapamycin-induced decrease in protein synthesis, a major energy-consuming process, may account for its ATP-saving effect. We propose that a mild reduction in protein synthesis may have the potential to treat mitochondria-related neurodegeneration.
Publisher: American Physiological Society
Date: 04-2005
Abstract: Substance P initiates locomotion when injected in the brain stem of mammals. This study examined the possible role of this peptide on the supraspinal locomotor command system in l reys. Substance P was bath applied or locally injected into an in vitro isolated brain stem, and the effects of the drug were examined on reticulospinal cells and on the occurrence of swimming in a semi-intact preparation. Bath applications of substance P induced sustained depolarizations occurring rhythmically in intracellularly recorded reticulospinal cells. Spiking activity was superimposed on the depolarizations and swimming was induced. The sustained depolarizations were abolished by tetrodotoxin, and substance P did not affect the membrane resistance of reticulospinal cells nor their firing properties, suggesting that it did not directly effect reticulospinal cells. To establish where the effects were exerted, successive lesions of the brain stem were made as well as local applications of the drug in the brain stem. Removing the mesencephalon abolished the sustained depolarizations, whereas large ejections of the drug in the mesencephalon excited reticulospinal cells and elicited bouts of swimming. More local injections into the mesencephalic locomotor region (MLR) also elicited swimming. After an injection of substance P, the current threshold needed to induce locomotion by MLR stimulation was decreased, and the size of the postsynaptic responses of reticulospinal cells to MLR stimulation was increased. Substance P also reduced the frequency of miniature spontaneous postsynaptic currents in reticulospinal cells. Taken together, these results suggest that substance P plays a neuromodulatory role on the brain stem locomotor networks of l reys.
Publisher: Proceedings of the National Academy of Sciences
Date: 28-05-2015
Publisher: Springer Science and Business Media LLC
Date: 13-05-2012
DOI: 10.1038/NN.3108
Publisher: Frontiers Media SA
Date: 11-06-2019
Publisher: eLife Sciences Publications, Ltd
Date: 04-03-2016
Publisher: Elsevier BV
Date: 03-2023
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 2009
DOI: 10.1167/9.1.20
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 18-10-2022
DOI: 10.1038/S41531-022-00400-0
Abstract: Complex genetic predispositions accelerate the chronic degeneration of midbrain substantia nigra neurons in Parkinson’s disease (PD). Deciphering the human molecular makeup of PD pathophysiology can guide the discovery of therapeutics to slow the disease progression. However, insights from human postmortem brain studies only portray the latter stages of PD, and there is a lack of data surrounding molecular events preceding the neuronal loss in patients. We address this gap by identifying the gene dysregulation of live midbrain neurons reprogrammed in vitro from the skin cells of 42 in iduals, including sporadic and familial PD patients and matched healthy controls. To minimize bias resulting from neuronal reprogramming and RNA-seq methods, we developed an analysis pipeline integrating PD transcriptomes from different RNA-seq datasets (unsorted and sorted bulk vs. single-cell and Patch-seq) and reprogramming strategies (induced pluripotency vs. direct conversion). This PD cohort’s transcriptome is enriched for human genes associated with known clinical phenotypes of PD, regulation of locomotion, bradykinesia and rigidity. Dysregulated gene expression emerges strongest in pathways underlying synaptic transmission, metabolism, intracellular trafficking, neural morphogenesis and cellular stress/immune responses. We confirmed a synaptic impairment with patch-cl ing and identified pesticides and endoplasmic reticulum stressors as the most significant gene-chemical interactions in PD. Subsequently, we associated the PD transcriptomic profile with candidate pharmaceuticals in a large database and a registry of current clinical trials. This study highlights human transcriptomic pathways that can be targeted therapeutically before the irreversible neuronal loss. Furthermore, it demonstrates the preclinical relevance of unbiased large transcriptomic assays of reprogrammed patient neurons.
Publisher: Springer Science and Business Media LLC
Date: 18-12-2016
DOI: 10.1038/MP.2015.202
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.NEUROSCIENCE.2008.09.057
Abstract: In anesthetized and immobilized domestic cats, we have studied the effects of brief reversible inactivation (by cooling to 10 degrees C) of the ipsilateral or contralateral postero-temporal visual (PTV) cortices on: 1) the magnitude of spike-responses of neurons in striate cortex (cytoarchitectonic area 17, area V1) to optimized sine-wave modulated contrast-luminosity gratings confined to the classical receptive fields (CRFs) and 2) the relative strengths of modulation of CRF-induced spike-responses by gratings extending into the extra-classical receptive field (ECRF). Consistent with our previous reports (Bardy et al., 2006 Huang et al., 2007), inactivation of ipsilateral PTV cortex (presumed homologue of primate infero-temporal cortex) resulted in significant reversible changes (almost all substantial reductions) in the magnitude of spike-responses to CRF-confined stimuli in about half of the V1 neurones. Similarly, in half of the present s le, inactivation of ipsilateral PTV cortex resulted in significant reversible changes (in over 70% of cases, reduction) in the relative strength of ECRF modulation of the CRF-induced spike-responses. By contrast, despite the fact that receptive fields of all V1 cells tested were located within 5 degrees of representation of the zero vertical meridian, inactivation of contralateral PTV cortex only rarely resulted in significant (yet invariably small) changes in the magnitude of spike-responses to CRF-confined stimuli or significant (again invariably small) changes in the relative strength of ECRF modulation of spike-responses. Thus, the ipsilateral, but not contralateral, 'higher-order' visual cortical areas make significant contribution not only to the magnitude of CRF-induced spike-responses but also to the relative strengths of ECRF-induced modulation of the spike-responses of V1 neurons. Therefore, the feedback signals originating from the ipsilateral higher-order cortical areas appear to make an important contribution to contextual modulation of responses of neurons in the primary visual cortices.
Publisher: Society for Neuroscience
Date: 11-01-2021
DOI: 10.1523/JNEUROSCI.1653-20.2020
Abstract: Single-cell transcriptomic approaches are revolutionizing neuroscience. Integrating this wealth of data with morphology and physiology, for the comprehensive study of neuronal biology, requires multiplexing gene expression data with complementary techniques. To meet this need, multiple groups in parallel have developed “Patch-seq,” a modification of whole-cell patch-cl protocols that enables mRNA sequencing of cell contents after electrophysiological recordings from in idual neurons and morphologic reconstruction of the same cells. In this review, we first outline the critical technical developments that enabled robust Patch-seq experimental efforts and analytical solutions to interpret the rich multimodal data generated. We then review recent applications of Patch-seq that address novel and long-standing questions in neuroscience. These include the following: (1) targeted study of specific neuronal populations based on their anatomic location, functional properties, lineage, or a combination of these factors (2) the compilation and integration of multimodal cell type atlases and (3) the investigation of the molecular basis of morphologic and functional ersity. Finally, we highlight potential opportunities for further technical development and lines of research that may benefit from implementing the Patch-seq technique. As a multimodal approach at the intersection of molecular neurobiology and physiology, Patch-seq is uniquely positioned to directly link gene expression to brain function.
Publisher: Proceedings of the National Academy of Sciences
Date: 18-07-2012
Abstract: The finding that certain somatic cells can be directly converted into cells of other lineages by the delivery of specific sets of transcription factors paves the way to novel therapeutic applications. Here we show that human cord blood (CB) CD133 + cells lose their hematopoietic signature and are converted into CB-induced neuronal-like cells (CB-iNCs) by the ectopic expression of the transcription factor Sox2, a process that is further augmented by the combination of Sox2 and c-Myc. Gene-expression analysis, immunophenotyping, and electrophysiological analysis show that CB-iNCs acquire a distinct neuronal phenotype characterized by the expression of multiple neuronal markers. CB-iNCs show the ability to fire action potentials after in vitro maturation as well as after in vivo transplantation into the mouse hippoc us. This system highlights the potential of CB cells and offers an alternative means to the study of cellular plasticity, possibly in the context of drug screening research and of future cell-replacement therapies.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 27-10-2023
Publisher: AIP Publishing
Date: 15-11-2018
DOI: 10.1063/1.5045124
Abstract: Stem cell-derived brain organoids provide a powerful platform for systematic studies of tissue functional architecture and the development of personalized therapies. Here, we review key advances at the interface of soft matter and stem cell biology on synthetic alternatives to extracellular matrices. We emphasize recent biomaterial-based strategies that have been proven advantageous towards optimizing organoid growth and controlling the geometrical, biomechanical, and biochemical properties of the organoid's three-dimensional environment. We highlight systems that have the potential to increase the translational value of region-specific brain organoid models suitable for different types of manipulations and high-throughput applications.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-05-2018
DOI: 10.1126/SCITRANSLMED.AAM6651
Abstract: The use of autologous (or syngeneic) cells derived from induced pluripotent stem cells (iPSCs) holds great promise for future clinical use in a wide range of diseases and injuries. It is expected that cell replacement therapies using autologous cells would forego the need for immunosuppression, otherwise required in allogeneic transplantations. However, recent studies have shown the unexpected immune rejection of undifferentiated autologous mouse iPSCs after transplantation. Whether similar immunogenic properties are maintained in iPSC-derived lineage-committed cells (such as neural precursors) is relatively unknown. We demonstrate that syngeneic porcine iPSC-derived neural precursor cell (NPC) transplantation to the spinal cord in the absence of immunosuppression is associated with long-term survival and neuronal and glial differentiation. No tumor formation was noted. Similar cell engraftment and differentiation were shown in spinally injured transiently immunosuppressed swine leukocyte antigen (SLA)-mismatched allogeneic pigs. These data demonstrate that iPSC-NPCs can be grafted into syngeneic recipients in the absence of immunosuppression and that temporary immunosuppression is sufficient to induce long-term immune tolerance after NPC engraftment into spinally injured allogeneic recipients. Collectively, our results show that iPSC-NPCs represent an alternative source of transplantable NPCs for the treatment of a variety of disorders affecting the spinal cord, including trauma, ischemia, or amyotrophic lateral sclerosis.
Publisher: Frontiers Media SA
Date: 2010
Publisher: Springer Science and Business Media LLC
Date: 08-2016
DOI: 10.1038/NATURE19067
Location: United States of America
Start Date: 07-2023
End Date: 06-2027
Amount: $1,145,629.00
Funder: Australian Research Council
View Funded ActivityStart Date: 08-2020
End Date: 12-2020
Amount: $620,000.00
Funder: Australian Research Council
View Funded Activity