RESUMEN
Cell replacement therapies for Parkinson's disease (PD) based on transplantation of pluripotent stem cell-derived dopaminergic neurons are now entering clinical trials. Here, we present quality, safety, and efficacy data supporting the first-in-human STEM-PD phase I/IIa clinical trial along with the trial design. The STEM-PD product was manufactured under GMP and quality tested in vitro and in vivo to meet regulatory requirements. Importantly, no adverse effects were observed upon testing of the product in a 39-week rat GLP safety study for toxicity, tumorigenicity, and biodistribution, and a non-GLP efficacy study confirmed that the transplanted cells mediated full functional recovery in a pre-clinical rat model of PD. We further observed highly comparable efficacy results between two different GMP batches, verifying that the product can be serially manufactured. A fully in vivo-tested batch of STEM-PD is now being used in a clinical trial of 8 patients with moderate PD, initiated in 2022.
Asunto(s)
Células Madre Embrionarias Humanas , Enfermedad de Parkinson , Humanos , Ratas , Animales , Enfermedad de Parkinson/terapia , Distribución Tisular , Diferenciación Celular/fisiología , Trasplante de Células Madre/métodos , Neuronas Dopaminérgicas/fisiologíaRESUMEN
Neuronal loss and axonal demyelination underlie long-term functional impairments in patients affected by brain disorders such as ischemic stroke. Stem cell-based approaches reconstructing and remyelinating brain neural circuitry, leading to recovery, are highly warranted. Here, we demonstrate the in vitro and in vivo production of myelinating oligodendrocytes from a human induced pluripotent stem cell (iPSC)-derived long-term neuroepithelial stem (lt-NES) cell line, which also gives rise to neurons with the capacity to integrate into stroke-injured, adult rat cortical networks. Most importantly, the generated oligodendrocytes survive and form myelin-ensheathing human axons in the host tissue after grafting onto adult human cortical organotypic cultures. This lt-NES cell line is the first human stem cell source that, after intracerebral delivery, can repair both injured neural circuitries and demyelinated axons. Our findings provide supportive evidence for the potential future use of human iPSC-derived cell lines to promote effective clinical recovery following brain injuries.
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Células Madre Pluripotentes Inducidas , Humanos , Ratas , Adulto , Animales , Diferenciación Celular/fisiología , Neuronas , Oligodendroglía/metabolismo , Axones/fisiología , Vaina de Mielina/fisiologíaRESUMEN
In the early 2000s, some children in asylum seeking families in Sweden showed severe reduction in function, including pervasive refusal to eat, drink, walk, talk or care for themselves. In 2014 this was to be named the resignation syndrome (ICD-10 F32.3A). The purpose of our study was to compare education and health-related outcomes over time between those with and without these symptoms, in a group of children from Central Asia who have been asylum seekers and received a residence permit in Sweden. We found that between the years 2005-2012, in the child and adolescent mental health services (CAMHS) in the Stockholm Region, 103 children showed symptoms of resignation, of whom 43 (43%) showed the most severe symptoms. Children with resignation syndrome assessed and cared for by CAMHS had similar need of outpatient care as other children of the same origin who had been treated by CAMHS for other conditions. They did not have an increased need for inpatient care compared with other children of the same origin, and they passed upper secondary school and past-secondary education to the same extent as other children of the same origin.
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Refugiados , Adolescente , Atención Ambulatoria , Niño , Humanos , Suecia/epidemiología , SíndromeRESUMEN
The ISSCR has developed the Informed Consent Standards for Human Fetal Tissue Donation and Research to promote uniformity and transparency in tissue donation and collection. This standard is designed to assist those working with and overseeing the regulation of such tissue and reassure the wider community and public.
Asunto(s)
Consentimiento Informado , Obtención de Tejidos y Órganos , Feto , HumanosRESUMEN
Fibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employing in vivo lineage tracing, we report that in all mouse models that develop fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes. Perivascular cells with a type A pericyte marker profile also exist in the human brain and spinal cord. We uncover type A pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.
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Sistema Nervioso Central/patología , Cicatriz/patología , Pericitos/patología , Envejecimiento/fisiología , Animales , Astrocitos/patología , Lesiones Traumáticas del Encéfalo/patología , Isquemia Encefálica/patología , Neoplasias Encefálicas/patología , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Matriz Extracelular/metabolismo , Fibroblastos/patología , Fibrosis , Glioblastoma/patología , Humanos , Accidente Cerebrovascular Isquémico/patología , Ratones Endogámicos C57BL , Ratones Transgénicos , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Médula Espinal/patología , Médula Espinal/ultraestructura , Traumatismos de la Médula Espinal/patología , Células del Estroma/patologíaRESUMEN
Upcoming clinical trials assessing transplantation of stem cell-derived dopaminergic neurons into the striatum in patients with Parkinson's disease could generate groundbreaking results on neuronal replacement in the human brain. However, as highlighted here, the road toward a clinically competitive treatment for this multisystem disorder will probably be long and winding.
Asunto(s)
Enfermedad de Parkinson , Neuronas Dopaminérgicas , Células Madre Embrionarias , Humanos , Motivación , Enfermedad de Parkinson/terapia , Trasplante de Células MadreRESUMEN
Several neurodegenerative diseases cause loss of cortical neurons, leading to sensory, motor, and cognitive impairments. Studies in different animal models have raised the possibility that transplantation of human cortical neuronal progenitors, generated from pluripotent stem cells, might be developed into a novel therapeutic strategy for disorders affecting cerebral cortex. For example, we have shown that human long-term neuroepithelial-like stem (lt-NES) cell-derived cortical neurons, produced from induced pluripotent stem cells and transplanted into stroke-injured adult rat cortex, improve neurological deficits and establish both afferent and efferent morphological and functional connections with host cortical neurons. So far, all studies with human pluripotent stem cell-derived neurons have been carried out using xenotransplantation in animal models. Whether these neurons can integrate also into adult human brain circuitry is unknown. Here, we show that cortically fated lt-NES cells, which are able to form functional synaptic networks in cell culture, differentiate to mature, layer-specific cortical neurons when transplanted ex vivo onto organotypic cultures of adult human cortex. The grafted neurons are functional and establish both afferent and efferent synapses with adult human cortical neurons in the slices as evidenced by immuno-electron microscopy, rabies virus retrograde monosynaptic tracing, and whole-cell patch-clamp recordings. Our findings provide the first evidence that pluripotent stem cell-derived neurons can integrate into adult host neural networks also in a human-to-human grafting situation, thereby supporting their potential future clinical use to promote recovery by neuronal replacement in the patient's diseased brain.
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Células Madre Pluripotentes Inducidas/trasplante , Neuronas/metabolismo , Animales , Diferenciación Celular , Humanos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Stroke triggers neurogenesis in the striatum in mice, with new neurons deriving in part from the nearby subventricular zone and in part from parenchymal astrocytes. The initiation of neurogenesis by astrocytes within the striatum is triggered by reduced Notch-signaling, and blocking this signaling pathway by deletion of the gene encoding the obligate Notch coactivator Rbpj is sufficient to activate neurogenesis by striatal astrocytes in the absence of an injury. Here we report that blocking Notch-signaling in stroke increases the neurogenic response to stroke 3.5-fold in mice. Deletion of Rbpj results in the recruitment of a larger number of parenchymal astrocytes to neurogenesis and over larger areas of the striatum. These data suggest inhibition of Notch-signaling as a potential translational strategy to promote neuronal regeneration after stroke.
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Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Neurogénesis , Receptores Notch/metabolismo , Transducción de Señal , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Animales , Astrocitos/metabolismo , Astrocitos/patología , Recuento de Células , Linaje de la Célula , Tamaño de la Célula , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/patologíaRESUMEN
Growth factors promote plasticity in injured brain and improve impaired functions. For clinical application, efficient approaches for growth factor delivery into the brain are necessary. Poly(ester amide) (PEA)-derived microspheres (MS) could serve as vehicles due to their thermal and mechanical properties, biocompatibility and biodegradability. Vascular endothelial growth factor (VEGF) exerts both vascular and neuronal actions, making it suitable to stimulate post-stroke recovery. Here, PEA (composed of adipic acid, L-phenyl-alanine and 1,4-butanediol) MS were loaded with VEGF and injected intracerebrally in mice subjected to cortical stroke. Loaded MS provided sustained release of VEGF in vitro and, after injection, biologically active VEGF was released long-term, as evidenced by high VEGF immunoreactivity, increased VEGF tissue levels, and higher vessel density and more NG2+ cells in injured hemisphere of animals with VEGF-loaded as compared to non-loaded MS. Loaded MS gave rise to more rapid recovery of neurological score. Both loaded and non-loaded MS induced improvement in neurological score and adhesive removal test, probably due to anti-inflammatory action. In summary, grafted PEA MS can act as efficient vehicles, with anti-inflammatory action, for long-term delivery of growth factors into injured brain. Our data suggest PEA MS as a new tool for neurorestorative approaches with therapeutic potential.
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Amidas/química , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Microesferas , Poliésteres/química , Accidente Cerebrovascular/terapia , Implantes Absorbibles , Adipatos/química , Animales , Antiinflamatorios/química , Conducta Animal , Materiales Biocompatibles/química , Butileno Glicoles/química , Sistemas de Liberación de Medicamentos , Infarto de la Arteria Cerebral Media/cirugía , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica , Tamaño de la Partícula , Fenilalanina/química , Polímeros/química , Proteínas Recombinantes/química , Porcinos , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Stem cell transplantation can improve behavioral recovery after stroke in animal models but whether stem cell-derived neurons become functionally integrated into stroke-injured brain circuitry is poorly understood. Here we show that intracortically grafted human induced pluripotent stem (iPS) cell-derived cortical neurons send widespread axonal projections to both hemispheres of rats with ischemic lesions in the cerebral cortex. Using rabies virus-based transsynaptic tracing, we find that at 6 mo after transplantation, host neurons in the contralateral somatosensory cortex receive monosynaptic inputs from grafted neurons. Immunoelectron microscopy demonstrates myelination of the graft-derived axons in the corpus callosum and that their terminals form excitatory, glutamatergic synapses on host cortical neurons. We show that the stroke-induced asymmetry in a sensorimotor (cylinder) test is reversed by transplantation. Light-induced inhibition of halorhodopsin-expressing, grafted neurons does not recreate the impairment, indicating that its reversal is not due to neuronal activity in the graft. However, we find bilateral decrease of motor performance in the cylinder test after light-induced inhibition of either grafted or endogenous halorhodopsin-expressing cortical neurons, located in the same area, and after inhibition of endogenous halorhodopsin-expressing cortical neurons by exposure of their axons to light on the contralateral side. Our data indicate that activity in the grafted neurons, probably mediated through transcallosal connections to the contralateral hemisphere, is involved in maintaining normal motor function. This is an example of functional integration of efferent projections from grafted neurons into the stroke-affected brain's neural circuitry, which raises the possibility that such repair might be achievable also in humans affected by stroke.
Asunto(s)
Células Madre Pluripotentes Inducidas/fisiología , Infarto de la Arteria Cerebral Media/terapia , Actividad Motora/fisiología , Neuronas/trasplante , Corteza Somatosensorial/fisiopatología , Potenciales de Acción/fisiología , Animales , Técnicas de Observación Conductual , Conducta Animal/fisiología , Diferenciación Celular/fisiología , Línea Celular , Modelos Animales de Enfermedad , Humanos , Infarto de la Arteria Cerebral Media/etiología , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/fisiopatología , Masculino , Neuronas/fisiología , Optogenética , Técnicas de Placa-Clamp , Ratas , Recuperación de la Función , Corteza Somatosensorial/citología , Corteza Somatosensorial/patologíaRESUMEN
Human neurodegenerative disorders affect specific types of cortical neurons. Efficient protocols for the generation of such neurons for cell replacement, disease modeling and drug screening are highly warranted. Current methods for the production of cortical neurons from human embryonic stem (ES) cells are often time-consuming and inefficient, and the functional properties of the generated cells have been incompletely characterized. Here we have used transcription factor (TF) programming with the aim to induce rapid differentiation of human ES cells to layer-specific cortical neurons (hES-iNs). Three different combinations of TFs, NEUROGENIN 2 (NGN2) only, NGN2 plus Forebrain Embryonic Zinc Finger-Like Protein 2 (FEZF2), and NGN2 plus Special AT-Rich Sequence-Binding Protein 2 (SATB2), were delivered to human ES cells by lentiviral vectors. We observed only subtle differences between the TF combinations, which all gave rise to the formation of pyramidal-shaped cells, morphologically resembling adult human cortical neurons expressing cortical projection neuron (PN) markers and with mature electrophysiological properties. Using ex vivo transplantation to human organotypic cultures, we found that the hES-iNs could integrate into adult human cortical networks. We obtained no evidence that the hES-iNs had acquired a distinct cortical layer phenotype. Instead, our single-cell data showed that the hES-iNs, similar to fetal human cortical neurons, expressed both upper and deep layer cortical neuronal markers. Taken together, our findings provide evidence that TF programming can direct human ES cells towards cortical neurons but that the generated cells are transcriptionally profiled to generate both upper and deep layer cortical neurons. Therefore, most likely additional cues will be needed if these cells should adopt a specific cortical layer and area identity.
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Células Madre Embrionarias Humanas/citología , Células Madre Embrionarias Humanas/metabolismo , Neuronas/citología , Neuronas/metabolismo , Factores de Transcripción/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Biomarcadores/metabolismo , Diferenciación Celular , Línea Celular , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Vectores Genéticos , Células Madre Embrionarias Humanas/trasplante , Humanos , Técnicas In Vitro , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neurogénesis , Técnicas de Cultivo de Órganos , Células Piramidales/citología , Células Piramidales/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factores de Transcripción/genéticaRESUMEN
In this issue of Cell Stem Cell, Peruzzotti-Jametti et al. (2018) demonstrate how neural stem cells, transplanted in a mouse model of multiple sclerosis, respond to extracellular succinate and modulate neuroinflammation by releasing anti-inflammatory prostaglandin E2 and scavenging succinate. This mechanism reduces CNS damage and ameliorates motor impairment.
Asunto(s)
Células-Madre Neurales , Ácido Succínico , Animales , Modelos Animales de Enfermedad , Macrófagos , RatonesRESUMEN
Induced pluripotent stem cells (iPSCs) or their progeny, derived from human somatic cells, can give rise to functional improvements after intracerebral transplantation in animal models of stroke. Previous studies have indicated that reactive gliosis, which is associated with stroke, inhibits neurogenesis from both endogenous and grafted neural stem/progenitor cells (NSPCs) of rodent origin. Here we have assessed whether reactive astrocytes affect the fate of human iPSC-derived NSPCs transplanted into stroke-injured brain. Mice with genetically attenuated reactive gliosis (deficient for GFAP and vimentin) were subjected to cortical stroke and cells were implanted adjacent to the ischemic lesion one week later. At 8 weeks after transplantation, immunohistochemical analysis showed that attenuated reactive gliosis did not affect neurogenesis or commitment towards glial lineage of the grafted NSPCs. Our findings, obtained in a human-to-mouse xenograft experiment, provide evidence that the reactive gliosis in stroke-injured brain does not affect the formation of new neurons from intracortically grafted human iPSC-derived NSPCs. However, for a potential clinical translation of these cells in stroke, it will be important to clarify whether the lack of effect of reactive gliosis on neurogenesis is observed also in a human-to-human experimental setting.
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Gliosis/prevención & control , Células Madre Pluripotentes Inducidas/trasplante , Células-Madre Neurales/trasplante , Neurogénesis , Accidente Cerebrovascular/patología , Animales , Proteína Ácida Fibrilar de la Glía/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , MutaciónRESUMEN
BACKGROUND: Human fibroblasts can be directly converted to several subtypes of neurons, but cortical projection neurons have not been generated. METHODS: Here we screened for transcription factor combinations that could potentially convert human fibroblasts to functional excitatory cortical neurons. The induced cortical (iCtx) cells were analyzed for cortical neuronal identity using immunocytochemistry, single-cell quantitative polymerase chain reaction (qPCR), electrophysiology, and their ability to integrate into human neural networks in vitro and ex vivo using electrophysiology and rabies virus tracing. RESULTS: We show that a combination of three transcription factors, BRN2, MYT1L, and FEZF2, have the ability to directly convert human fibroblasts to functional excitatory cortical neurons. The conversion efficiency was increased to about 16% by treatment with small molecules and microRNAs. The iCtx cells exhibited electrophysiological properties of functional neurons, had pyramidal-like cell morphology, and expressed key cortical projection neuronal markers. Single-cell analysis of iCtx cells revealed a complex gene expression profile, a subpopulation of them displaying a molecular signature closely resembling that of human fetal primary cortical neurons. The iCtx cells received synaptic inputs from co-cultured human fetal primary cortical neurons, contained spines, and expressed the postsynaptic excitatory scaffold protein PSD95. When transplanted ex vivo to organotypic cultures of adult human cerebral cortex, the iCtx cells exhibited morphological and electrophysiological properties of mature neurons, integrated structurally into the cortical tissue, and received synaptic inputs from adult human neurons. CONCLUSIONS: Our findings indicate that functional excitatory cortical neurons, generated here for the first time by direct conversion of human somatic cells, have the capacity for synaptic integration into adult human cortex.
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Corteza Cerebral/citología , Células Madre Embrionarias/citología , Fibroblastos/citología , Neurogénesis , Neuronas/citología , Adulto , Células Cultivadas , Células Madre Embrionarias/metabolismo , Potenciales Postsinápticos Excitadores , Fibroblastos/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Factores del Dominio POU/genética , Factores del Dominio POU/metabolismo , Sinapsis/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Ischemic stroke, caused by middle cerebral artery occlusion, leads to long-lasting formation of new striatal neurons from neural stem/progenitor cells (NSPCs) in the subventricular zone (SVZ) of adult rodents. Concomitantly with this neurogenic response, SVZ exhibits activation of resident microglia and infiltrating monocytes. Here we show that depletion of circulating monocytes, using the anti-CCR2 antibody MC-21 during the first week after stroke, enhances striatal neurogenesis at one week post-insult, most likely by increasing short-term survival of the newly formed neuroblasts in the SVZ and adjacent striatum. Blocking monocyte recruitment did not alter the volume of the ischemic lesion but gave rise to reduced astrocyte activation in SVZ and adjacent striatum, which could contribute to the improved neuroblast survival. A similar decrease of astrocyte activation was found in and around human induced pluripotent stem cell (iPSC)-derived NSPCs transplanted into striatum at one week after stroke in monocyte-depleted mice. However, there was no effect on neurogenesis in the graft as determined 8weeks after implantation. Our findings demonstrate, for the first time, that a specific cellular component of the early inflammatory reaction in SVZ and adjacent striatum following stroke, i.e., infiltrating monocytes, compromises the short-term neurogenic response neurogenesis from endogenous NSPCs.
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Encéfalo/fisiología , Células Madre Pluripotentes Inducidas/fisiología , Monocitos/fisiología , Células-Madre Neurales/fisiología , Neurogénesis/fisiología , Accidente Cerebrovascular/terapia , Factores de Edad , Animales , Encéfalo/citología , Humanos , Células Madre Pluripotentes Inducidas/trasplante , Masculino , Ratones , Ratones Endogámicos C57BL , Células-Madre Neurales/trasplante , Trasplante de Células Madre/métodos , Accidente Cerebrovascular/patologíaRESUMEN
BACKGROUND: Choroid plexus (CP) supports the entry of monocyte-derived macrophages (MDMs) to the central nervous system in animal models of traumatic brain injury, spinal cord injury, and Alzheimer's disease. Whether the CP is involved in the recruitment of MDMs to the injured brain after ischemic stroke is unknown. METHODS: Adult male C57BL/6 mice were subjected to focal cortical ischemia by permanent occlusion of the distal branch of the right middle cerebral artery. Choroid plexus tissues were collected and analyzed for Vcam1, Madcam1, Cx3cl1, Ccl2, Nt5e, and Ifnγ expression at different timepoints after stroke using qPCR. Changes of MDMs in CP and cerebrospinal fluid (CSF) at 1 day and 3 days after stroke were analyzed using flow cytometry. Infiltration of MDMs into CP and CSF were validated using ß-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. CD115+ monocytes were isolated using a magnetic cell separation system from bone marrow of Cx3cr1-GFP or wild-type C57BL/6 donor mice. The freshly isolated monocytes or M2-like MDMs primed in vitro with IL4 and IL13 were stereotaxically injected into the lateral ventricle of stroke-affected mice to trace for their migration into ischemic hemisphere or to assess their effect on post-stroke recovery using open field, corridor, and active avoidance behavioral tests. RESULTS: We found that CP responded to cortical stroke by upregulation of gene expression for several possible mediators of MDM trafficking and, concomitantly, MDMs increased in CP and cerebrospinal fluid (CSF). We then confirmed that MDMs infiltrated from blood into CP and CSF after the insult using ß-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. When MDMs were directly administered into CSF following stroke, they homed to the ischemic hemisphere. If they had been primed in vitro prior to their administration to become M2-like macrophages, they promoted post-stroke recovery of motor and cognitive function without influencing infarct volume. CONCLUSIONS: Our findings suggest the possibility that autologous transplantation of M2-like MDMs into CSF might be developed into a new strategy for promoting recovery also in patients with stroke.
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Líquido Cefalorraquídeo/metabolismo , Plexo Coroideo/patología , Macrófagos/patología , Monocitos/patología , Accidente Cerebrovascular/patología , Actinas/genética , Actinas/metabolismo , Animales , Antígenos CD/metabolismo , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Proteínas de Unión al Calcio/metabolismo , Modelos Animales de Enfermedad , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Microfilamentos/metabolismo , Monocitos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Accidente Cerebrovascular/fisiopatología , Factores de Tiempo , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
Somatic cells such as fibroblasts, reprogrammed to induced pluripotent stem cells, can be used to generate neural stem/progenitor cells or neuroblasts for transplantation. In this review, we summarize recent studies demonstrating that when grafted intracerebrally in animal models of stroke, reprogrammed neurons improve function, probably by several different mechanisms, e.g., trophic actions, modulation of inflammation, promotion of angiogenesis, cellular and synaptic plasticity, and neuroprotection. In our own work, we have shown that human skin-derived reprogrammed neurons, fated to cortical progeny, integrate in stroke-injured neuronal network and form functional afferent synapses with host neurons, responding to peripheral sensory stimulation. However, whether neuronal replacement plays a role for the improvement of sensory, motor, and cognitive deficits after transplantation of reprogrammed neurons is still unclear. We conclude that further preclinical studies are needed to understand the therapeutic potential of grafted reprogrammed neurons and to define a road map for their clinical translation in stroke.
Asunto(s)
Células Madre Pluripotentes Inducidas/trasplante , Células-Madre Neurales/trasplante , Accidente Cerebrovascular/terapia , Animales , Diferenciación Celular , Reprogramación Celular , Humanos , Neuronas/citología , SinapsisRESUMEN
BACKGROUND: Intracerebral transplantation of human induced pluripotent stem cells (iPSCs) can ameliorate behavioral deficits in animal models of stroke. How the ischemic lesion affects the survival of the transplanted cells, their proliferation, migration, differentiation, and function is only partly understood. METHODS: Here we have assessed the influence of the stroke-induced injury on grafts of human skin iPSCs-derived long-term neuroepithelial-like stem cells using transplantation into the rostral migratory stream (RMS), adjacent to the neurogenic subventricular zone, in adult rats as a model system. RESULTS: We show that the occurrence of an ischemic lesion, induced by middle cerebral artery occlusion, in the striatum close to the transplant does not alter the survival, proliferation, or generation of neuroblasts or mature neurons or astrocytes from the grafted progenitors. In contrast, the migration and axonal projection patterns of the transplanted cells are markedly influenced. In the intact brain, the grafted cells send many fibers to the main olfactory bulb through the RMS and a few of them migrate in the same direction, reaching the first one third of this pathway. In the stroke-injured brain, on the other hand, the grafted cells only migrate toward the ischemic lesion and virtually no axonal outgrowth is observed in the RMS. CONCLUSIONS: Our findings indicate that signals released from the stroke-injured area regulate the migration of and fiber outgrowth from grafted human skin-derived neural progenitors and overcome the influence on these cellular properties exerted by the neurogenic area/RMS in the intact brain.
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Células Madre Pluripotentes Inducidas/trasplante , Células-Madre Neurales/trasplante , Neurogénesis , Accidente Cerebrovascular/terapia , Animales , Astrocitos/metabolismo , Axones/metabolismo , Encéfalo/patología , Diferenciación Celular/genética , Humanos , Infarto de la Arteria Cerebral Media , Células-Madre Neurales/inmunología , Neuronas/inmunología , Neuronas/patología , Ratas , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/patologíaRESUMEN
The efforts to develop a dopamine cell replacement therapy for Parkinson's disease have spanned over more than three decades. Based on almost 10 years of transplantation studies in animal models, the first patients receiving grafts of fetal-derived dopamine neuroblasts were operated in Lund in 1987. Over the following two decades, a total of 18 patients were transplanted and followed closely by our team with mixed but also very encouraging results. In this article we tell the story of how the preclinical and clinical transplantation program in Lund evolved. We recall the excitement when we obtained the first evidence for survival and function of transplanted neurons in the diseased human brain. We also remember the setbacks that we have experienced during these 30 years and discuss the very interesting developments that are now taking place in this exciting field.
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Neuronas Dopaminérgicas/trasplante , Trasplante de Tejido Fetal/historia , Células-Madre Neurales/trasplante , Enfermedad de Parkinson/terapia , Trasplante de Células Madre/historia , Animales , Historia del Siglo XX , Historia del Siglo XXI , Humanos , SueciaRESUMEN
Preclinical studies suggest that stem cell therapy (SCT) may improve sensorimotor recovery after stroke. Upper extremity motor impairment (UEMI) is common after stroke, often entailing substantial disability. To evaluate the feasibility of post-stroke UEMI as a target for SCT, we examined a selected sample of stroke patients potentially suitable for SCT, aiming to assess the frequency and recovery of UEMI, as well as its relation to activity limitations and participation restrictions. Patients aged 20-75 years with first-ever ischemic stroke, and National Institutes of Health Stroke Scale (NIHSS) scores 1-18, underwent brain diffusion-weighted MRI within 4 days of stroke onset (n = 108). Survivors were followed up after 3-5 years, including assessment with NIHSS, Fugl-Meyer assessment of upper extremity (FMA-UE), modified Rankin Scale (mRS), and Stroke Impact Scale (SIS). UEMI was defined as NIHSS arm/hand score ≥1. UEMI recovery was evaluated with change in NIHSS arm/hand scores between baseline and follow-up. Of 97 survivors, 84 were available to follow-up. Among 76 subjects (of 84) without recurrent stroke, 41 had UEMI at baseline of which 10 had residual UEMI at follow-up. The FMA-UE showed moderate-severe impairment in seven of 10 survivors with residual UEMI. UEMI was correlated to mRS (r s = 0.49, p < 0.001) and the SIS social participation domain (r s = -0.38, p = 0.001). Nearly 25% of the subjects with UEMI at baseline had residual impairment after 3-5 years, whereas about 75% showed complete recovery. Most of the subjects with residual UEMI had moderate-severe impairment, which correlated strongly to dependency in daily activities and social participation restrictions. Our findings suggest that SCT targeting post-stroke UEMI may be clinically valuable with significant meaningful benefits for patients but also emphasize the need of early prognostication to detect patients that will have residual impairment in order to optimize patient selection for SCT.