Insights into Human-Induced Pluripotent Stem Cell-Derived Astrocytes in Neurodegenerative Disorders

Kumar, Manoj; Nguyen, Nhung Thi Phuong; Milanese, Marco; Bonanno, Giambattista

doi:10.3390/biom12030344

Cited by 12 publications

(14 citation statements)

References 140 publications

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“…As an alternative to using NSC/NPC, it is possible to appropriately differentiated stromal/stem cells isolated from other environment alone (i.e., MSC) or in combination with NSC [ 83 ], induced pluripotent stem cells (iPSC) derived from an appropriate somatic cell [ 84 , 85 , 86 , 87 ], or extracellular vesicles (EV) derived from MSC or a relevant cell cultured under optimal in vitro culture conditions [ 88 , 89 ]. The latter are becoming an important avenue of research as they are not immunogenetic, can contain a range of molecules that can enhance endogenous cell repair of the damaged tissue, and could therefore be used in non-autologous application, which would overcome potential limitations associated with autologous materials.…”

Section: Limitations Regarding Use Of Brain-associated Nscmentioning

confidence: 99%

Use of Brain-Derived Stem/Progenitor Cells and Derived Extracellular Vesicles to Repair Damaged Neural Tissues: Lessons Learned from Connective Tissue Repair Regarding Variables Limiting Progress and Approaches to Overcome Limitations

Hart

2023

IJMS

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Pluripotent neural stem or progenitor cells (NSC/NPC) have been reported in the brains of adult preclinical models for decades, as have mesenchymal stem/stromal cells (MSC) been reported in a variety of tissues from adults. Based on their in vitro capabilities, these cell types have been used extensively in attempts to repair/regenerate brain and connective tissues, respectively. In addition, MSC have also been used in attempts to repair compromised brain centres. However, success in treating chronic neural degenerative conditions such as Alzheimer’s disease, Parkinson’s disease, and others with NSC/NPC has been limited, as have the use of MSC in the treatment of chronic osteoarthritis, a condition affecting millions of individuals. However, connective tissues are likely less complex than neural tissues regarding cell organization and regulatory integration, but some insights have been gleaned from the studies regarding connective tissue healing with MSC that may inform studies attempting to initiate repair and regeneration of neural tissues compromised acutely or chronically by trauma or disease. This review will discuss the similarities and differences in the applications of NSC/NPC and MSC, where some lessons have been learned, and potential approaches that could be used going forward to enhance progress in the application of cellular therapy to facilitate repair and regeneration of complex structures in the brain. In particular, variables that may need to be controlled to enhance success are discussed, as are different approaches such as the use of extracellular vesicles from stem/progenitor cells that could be used to stimulate endogenous cells to repair the tissues rather than consider cell replacement as the primary option. Caveats to all these efforts relate to whether cellular repair initiatives will have long-term success if the initiators for neural diseases are not controlled, and whether such cellular initiatives will have long-term success in a subset of patients if the neural diseases are heterogeneous and have multiple etiologies.

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Section: Limitations Regarding Use Of Brain-associated Nscmentioning

confidence: 99%

Use of Brain-Derived Stem/Progenitor Cells and Derived Extracellular Vesicles to Repair Damaged Neural Tissues: Lessons Learned from Connective Tissue Repair Regarding Variables Limiting Progress and Approaches to Overcome Limitations

Hart

2023

IJMS

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“…iPSCs were first discovered by Takahashi and Yamanaka in 2006 from adult somatic cells via integrating four factors (Sox2, Oct3/4, Klf4, and cMyc) [ 118 ]. Till date, with the great capacity of self-renewal and differentiation into all somatic cell types, iPSC-based cell therapy has been widely investigated, and their potential in the treatment of neurodegenerative diseases has been studied [ 119 , 120 ]. Rajasingh et al have compared human iPSC-derived MSCs (iMSCs) and MSCs and found that iMSCs still maintained MSC characteristics without any chromosomal abnormalities even at later passages, while MSCs started to lose their characteristics at that time, indicating that iMSCs might be an alternative cell type to MSCs for the treatment of various diseases [ 121 ].…”

Section: Exosomes-based Therapy and Application In Cerebral I/r Injurymentioning

confidence: 99%

Exosomes in Cerebral Ischemia-Reperfusion Injury: Current Perspectives and Future Challenges

Zhou

Liu

et al. 2022

Brain Sciences

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Cerebral ischemia impedes the functional or metabolic demands of the central nervous system (CNS), which subsequently leads to irreversible brain damage. While recanalization of blocked vessels recovers cerebral blood flow, it can also aggravate brain injury, termed as ischemia/reperfusion (I/R) injury. Exosomes, nanometric membrane vesicles, attracted wide attention as carriers of biological macromolecules. In the brain, exosomes can be secreted by almost all types of cells, and their contents can be altered during the pathological and clinical processes of cerebral I/R injury. Herein, we will review the current literature on the possible role of cargos derived from exosomes and exosomes-mediated intercellular communication in cerebral I/R injury. The PubMed and Web of Science databases were searched through January 2015. The studies published in English were identified using search terms including “exosomes”, “cerebral ischemia-reperfusion injury”, “brain ischemia-reperfusion injury”, and “stroke”. We will also focus on the potential therapeutic effects of stem cell-derived exosomes and underlying mechanisms in cerebral I/R injury. Meanwhile, with the advantages of low immunogenicity and cytotoxicity, high bioavailability, and the capacity to pass through the blood–brain barrier, exosomes also attract more attention as therapeutic modalities for the treatment of cerebral I/R injury.

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“…Several possible human-like model systems have been described. Firstly, the development of human induced pluripotent stem cell (iPSC) technologies has transformed research into neurodegenerative diseases, allowing the generation of specific neural cell types from patients and healthy donors to model human disease (Kumar et al, 2022). Human iPSCs have been successfully differentiated into astrocytes and extensively studied (Kumar et al, 2022;Ren & Dunaevsky, 2021), however this approach is not without limitations.…”

Section: Introductionmentioning

confidence: 99%

“…Firstly, the development of human induced pluripotent stem cell (iPSC) technologies has transformed research into neurodegenerative diseases, allowing the generation of specific neural cell types from patients and healthy donors to model human disease (Kumar et al, 2022). Human iPSCs have been successfully differentiated into astrocytes and extensively studied (Kumar et al, 2022;Ren & Dunaevsky, 2021), however this approach is not without limitations. Protocols for generating human iPSC-derived astrocytes vary considerably, and are continuously being improved, with no single protocol having been widely accepted as the "gold standard" (Kumar et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Human iPSCs have been successfully differentiated into astrocytes and extensively studied (Kumar et al, 2022;Ren & Dunaevsky, 2021), however this approach is not without limitations. Protocols for generating human iPSC-derived astrocytes vary considerably, and are continuously being improved, with no single protocol having been widely accepted as the "gold standard" (Kumar et al, 2022). The resulting differentiated cells are therefore not standardised between research groups, affecting the reproducibility and relevance of findings.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Investigating the role that astrocytes play in mediating changes in synaptic health in Alzheimer’s disease

Johnson

Noble

Perez‐Nievas

2020

Alzheimer's & Dementia

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Background Previous results from our group showed that abeta‐stimulated astrocytes release factors that are detrimental to neurons. Our aim is to investigate and validate those factors. One cytokine in particular is shown to be increased after treatment with low concentrations of oligomeric abeta and has been associated with abnormal tau cleavage. We analysed the effect of the cytokine on neuronal health and complexity and on localisation of tau. We also investigated whether the change in phenotype of astrocytes in response to abeta depends on abeta internalisation, and which pathways are involved. Method Primary astrocytic and neuronal cultures were prepared from CD1 mice following standard protocols. Neurons were treated with the cytokine and/or its receptor antagonist and transfected with GFP to allow measurement of dendritic spine density and neurite complexity. Localisation of tau was examined in similarly treated neurons by immunocytochemistry. To investigate abeta internalisation, transgenic conditioned media containing abeta was collected from Tg2576 neurons, with medium from littermate wild type neurons as a control. Astrocytes were treated with conditioned media in the presence or absence of Dynasore, a small molecule inhibitor of dynamin GTPases, and abeta uptake assessed by immunocytochemistry. Result Exposure of neurons to the cytokine results in a reduction of dendritic spine density and neuronal complexity which is rescued when its receptor is blocked by a specific inhibitor. Exposure to the cytokine also seems to affect tau localisation in neurons, causing mislocalisation of tau from the axonal to the somatodendritic compartment. Preliminary data shows that astrocytes internalise abeta quite quickly following addition to the medium, at least in part through endocytosis. Conclusion The phenotype of astrocytes is altered in response to abeta, causing their secretion of molecules, including cytokines. Exposure of neurons to one of these cytokines causes reduced neuronal health and complexity, further confirming that factors released by astrocytes are synaptotoxic.

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Insights into Human-Induced Pluripotent Stem Cell-Derived Astrocytes in Neurodegenerative Disorders

Cited by 12 publications

References 140 publications

Use of Brain-Derived Stem/Progenitor Cells and Derived Extracellular Vesicles to Repair Damaged Neural Tissues: Lessons Learned from Connective Tissue Repair Regarding Variables Limiting Progress and Approaches to Overcome Limitations

Use of Brain-Derived Stem/Progenitor Cells and Derived Extracellular Vesicles to Repair Damaged Neural Tissues: Lessons Learned from Connective Tissue Repair Regarding Variables Limiting Progress and Approaches to Overcome Limitations

Exosomes in Cerebral Ischemia-Reperfusion Injury: Current Perspectives and Future Challenges

Investigating the role that astrocytes play in mediating changes in synaptic health in Alzheimer’s disease

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