Defined hydrogels for spinal cord organoids:challenges and potential applications

Organoids of the central nervous system,primarily derived from pluripotent stem cells or neural stem cells,are three-dimensional tissue cultures with self-organizing properties.When exposed to the right combinations of signals,they differentiate into a 3D tissue consisting of complex cytoarchitecture and native cell types,including various neuron subtypes and glial cells.These features closely mimic native tissues,making them invaluable for developmental studies and disease modeling.In recent years,spinal cord organoids(SCOs)have been developed to investigate spinal cord development,injuries,and various neurological disorders.As an integral part of the central nervous system,SCOs play a vital role and serve as a site for studying both neurodevelopment and neurodegenerative diseases.

Spinal cord organoids add an extra dimension to traditional motor neuron cultures

Since Lancaster et al.(2013)first described the formation of self-organizing cerebral organoids for modeling neurodevelopmental disorders,it became evident that three-dimensional(3D)neural organoid cultures are more superior systems for modeling neurodevelopment and neurodegeneration in human.The use of a spinning bioreactor to grow organoids allows better nutrient absorption and enhances formation of neuroepithelial-like zones,making it a great tool to study neurodevelopment and neurodegeneration.Neural organoids are 3D cell culture systems formed by proliferating,differentiating,migrating and self-organizing pools of neural progenitors.They mimic brain structures in their cell type composition,cytoarchitecture,and to some extent maturity and functionality(Lancaster et al.,2013).Because of these unique.

Replacing what’s lost: a new era of stem cell therapy for Parkinson’s disease

Background Stem cells hold tremendous promise for regenerative medicine because they can be expanded infinitely,giving rise to large numbers of differentiated cells required for transplantation.Stem cells can be derived from fetal sources,embryonic origins(embryonic stem cells or ESCs)or reprogrammed from adult cell types(induced pluripotent stem cells or iPSCs).One unique property of stem cells is their ability to be directed towards specific cell types of clinical interest,and can mature into functional cell types in vivo.While transplantations of fetal or ESC-derived tissues are known to illicit a host immunogenic response,autologous transplantations using cell types derived from one’s own iPSCs eliminate risks of tissue rejection and reduce the need for immunosuppressants.However,even with these benefits,cell therapy comes with significant hurdles that researchers are starting to overcome.In this review,we will discuss the various steps to ensure safety,efficacy and clinical practicality of cell replacement therapy in neurodegenerative diseases,in particular,Parkinson’s disease.Main body Parkinson’s disease(PD)results from a loss of dopaminergic neurons from the substantia nigra and is an ideal target for cell replacement therapy.Early trials using fetal midbrain material in the late 1980s have resulted in long term benefit for some patients,but there were multiple shortcomings including the non-standardization and quality control of the transplanted fetal material,and graft-induced dyskinesia that some patients experience as a result.On the other hand,pluripotent stem cells such as ESCs and iPSCs serve as an attractive source of cells because they can be indefinitely cultured and is an unlimited source of cells.Stem cell technologies and our understanding of the developmental potential of ESCs and iPSCs have deepened in recent years and a clinical trial for iPSC-derived dopaminergic cells is currently undergoing for PD patients in Japan.In this focused review,we will first provide a historical aspect of cell therapies in PD,and then discuss the various challenges pertaining to the safety and efficacy of stem cell-based cell transplantations,and how these hurdles were eventually overcome.Conclusion With the maturity of the iPSC technology,cell transplantation appears to be a safe and effective therapy.Grafts in non-human primates survive and remain functional for more than 2 years after transplantation,with no signs of tumorigenesis,indicating safety and efficacy of the treatment.However,immunosuppressants are still required because of the lack of“universal stem cells”that would not evoke an immune response.The results of ongoing and upcoming trials by a global consortium known as GForce-PD would be highly anticipated because the success of these trials would open up possibilities for using cell therapy for the treatment of PD and other degenerative diseases.

Deciphering lipid dysregulation in ALS:from mechanisms to translational medicine

Lipids,defined by low solubility in water and high solubility in nonpolar solvents,can be classified into fatty acids,glycerolipids,glycerophospholipids,sphingolipids,and sterols.Lipids not only regulate integrity and fluidity of biologi-cal membranes,but also serve as energy storage and bioactive molecules for signaling.Causal mutations in SPTLC1(serine palmitoyltransferase long chain subunit 1)gene within the lipogenic pathway have been identified in amyo-trophic lateral sclerosis(ALS),a paralytic and fatal motor neuron disease.Furthermore,lipid dysmetabolism within the central nervous system and circulation is associated with ALS.Here,we aim to delineate the diverse roles of different lipid classes and understand how lipid dysmetabolism may contribute to ALS pathogenesis.Among the different lipids,accumulation of ceramides,arachidonic acid,and lysophosphatidylcholine is commonly emerging as detri-mental to motor neurons.We end with exploring the potential ALS therapeutics by reducing these toxic lipids.

Remodeling of astrocyte secretome in amyotrophic lateral sclerosis:uncovering novel targets to combat astrocyte-mediated toxicity

Amyotrophic lateral sclerosis(ALS)is an adult-onset paralytic disease characterized by progressive degeneration of upper and lower motor neurons in the motor cortex,brainstem and spinal cord.Motor neuron degeneration is typically caused by a combination of intrinsic neuronal(cell autonomous)defects as well as extrinsic(non-cell autonomous)factors such as astrocyte-mediated toxicity.Astrocytes are highly plastic cells that react to their microenvironment to mediate relevant responses.In neurodegeneration,astrocytes often turn reactive and in turn secrete a slew of factors to exert pro-inflammatory and neurotoxic effects.Various efforts have been carried out to characterize the diseased astrocyte secretome over the years,revealing that pro-inflammatory chemokines,cytokines and microRNAs are the main players in mediating neuronal death.As metabolomic technologies mature,these studies begin to shed light on neurotoxic metabolites such as secreted lipids.In this focused review,we will discuss changes in the astrocyte secretome during ALS.In particular,we will discuss the components of the reactive astrocyte secretome that contribute to neuronal death in ALS.