HuCNS-SC Human NSCs Fail to Differentiate, Form Ectopic Clusters, and Provide No Cognitive Benefits in a Transgenic Model of Alzheimer's Disease

Marsh, Samuel E.; Yeung, Stephen T.; Torres, M.D. Martínez del Valle; Lau, Lydia; Davis, Joy; Monuki, Edwin S.; Poon, Wayne W.; Blurton‐Jones, Mathew

doi:10.1016/j.stemcr.2016.12.019

Cited by 52 publications

(61 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, very recent clinical trial data highlight critical issues with tissue‐source cells. Using tissue‐source neural stem cells (NSCs), two recent clinical trials reported surprisingly negative results despite previous animal studies demonstrating therapeutic efficacy . Reasons that could account for these unexpected disappointing results with regard to the cellular produce itself include inherent donor‐specific genetic differences and NSC heterogeneity, as well as extrinsic factors during the manufacturing process, which can all add to inconsistencies in the end product .…”

Section: Discussionmentioning

confidence: 99%

Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

Wang

Jiang²,

Ting

et al. 2018

Stem Cells

View full text Add to dashboard Cite

Multilineage tissue-source mesenchymal stem cells (MSCs) possess strong immunomodulatory properties and are excellent therapeutic agents, but require constant isolation from donors to combat replicative senescence. The differentiation of human induced pluripotent stem cells (iPSCs) into MSCs offers a renewable source of MSCs; however, reports on their immunomodulatory capacity have been discrepant. Using MSCs differentiated from iPSCs reprogrammed using diverse cell types and protocols, and in comparison to human embryonic stem cell (ESC)-MSCs and bone marrow (BM)-MSCs, we performed transcriptome analyses and assessed for functional immunomodulatory properties. Differentiation of MSCs from iPSCs results in decreased c-Myc expression and its downstream pathway along with a concomitant downregulation in the DNA replication pathway. All four lines of iPSC-MSCs can significantly suppress in vitro activated human peripheral blood mononuclear cell (PBMC) proliferation to a similar degree as ESC-MSCs and BM-MSCs, and modulate CD4 T lymphocyte fate from a type 1 helper T cell (Th1) and IL-17A-expressing (Th17) cell fate to a regulatory T cell (Treg) phenotype. Moreover, iPSC-MSCs significantly suppress cytotoxic CD8 T proliferation, activation, and differentiation into type 1 cytotoxic T (Tc1) and IL-17-expressing CD8 T (Tc17) cells. Coculture of activated PBMCs with human iPSC-MSCs results in an overall shift of secreted cytokine profile from a pro-inflammatory environment to a more immunotolerant milieu. iPSC-MSC immunomodulation was also validated in vivo in a mouse model of induced inflammation. These findings support that iPSC-MSCs possess low oncogenicity and strong immunomodulatory properties regardless of cell-of-origin or reprogramming method and are good potential candidates for therapeutic use. Stem Cells 2018;36:903-914.

show abstract

Section: Discussionmentioning

confidence: 99%

Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

Wang

Jiang²,

Ting

et al. 2018

Stem Cells

View full text Add to dashboard Cite

show abstract

“…Indeed, it is becoming increasingly clear that no two NSC lines are completely equivalent. Even when derived from similar source material using similar methods we have found disparate differences in NSC phenotype and behavior (Ager et al, 2015, Marsh et al, in press). It follows that identifying the optimal NSC line for clinical translation may be extremely challenging and that clinical grade NSC lines intended for trials need to be individually tested for efficacy and safety in appropriate animal models prior to translation.…”

Section: Remaining Challengesmentioning

confidence: 81%

Neural stem cell therapy for neurodegenerative disorders: The role of neurotrophic support

Marsh

Blurton‐Jones

2017

Neurochemistry International

Self Cite

150

View full text Add to dashboard Cite

Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease currently affect tens of millions of people worldwide. Unfortunately, as the world’s population ages, the incidence of many of these diseases will continue to rise and is expected to more than double by 2050. Despite significant research and a growing understanding of disease pathogenesis, only a handful of therapies are currently available and all of them provide only transient benefits. Thus, there is an urgent need to develop novel disease-modifying therapies to prevent the development or slow the progression of these debilitating disorders. A growing number of pre-clinical studies have suggested that transplantation of neural stem cells (NSCs) could offer a promising new therapeutic approach for neurodegeneration. While much of the initial excitement about this strategy focused on the use of NSCs to replace degenerating neurons, more recent studies have implicated NSC-mediated changes in neurotrophins as a major mechanism of therapeutic efficacy. In this mini-review we will discuss recent work that examines the ability of NSCs to provide trophic support to disease-effected neuronal populations and synapses in models of neurodegeneration. We will then also discuss some of key challenges that remain before NSC-based therapies for neurodegenerative diseases can be translated toward potential clinical testing.

show abstract

“…The establishment of a xeno-free system is increasingly important for preclinical investigations, as recent studies have reported the failure of clinical-grade NSCs in pre-clinical models of SCI (Anderson, Piltti, Hooshmand, Nishi, & Cummings, 2017) and Alzheimer's disease (Marsh et al, 2017), despite the efficacy of research-grade cells. To our best knowledge, this study is the first to report the successful derivation of forebrain OPCs from hPSCs under a xeno-free condition.…”

Section: Discussionmentioning

confidence: 99%

Xeno‐free culture for generation of forebrain oligodendrocyte precursor cells from human pluripotent stem cells

Hermanto

Maki

Takagi

et al. 2019

J of Neuroscience Research

View full text Add to dashboard Cite

Oligodendrocytes (OLs) show heterogeneous properties that depend on their location in the central nervous system (CNS). In this regard, the investigation of oligodendrocyte precursor cells (OPCs) derived from human pluripotent stem cells (hPSCs) should be reconsidered, particularly in cases of brain‐predominant disorders for which brain‐derived OPCs are more appropriate than spinal cord‐derived OPCs. Furthermore, animal‐derived components are responsible for culture variability in the derivation and complicate clinical translation. In the present study, we established a xeno‐free system to induce forebrain OPCs from hPSCs. We induced human forebrain neural stem cells (NSCs) on Laminin 511‐E8 and directed the differentiation to the developmental pathway for forebrain OLs with SHH and FGF signaling. OPCs were characterized by the expression of OLIG2, NKX2.2, SOX10, and PDGFRA, and subsequent maturation into O4+ cells. In vitro characterization showed that >85% of the forebrain OPCs (O4+) underwent maturation into OLs (MBP+) 3 weeks after mitogen removal. Upon intracranial transplantation, the OPCs survived, dispersed in the corpus callosum, and matured into (GSTπ+) OLs in the host brains 3 months after transplantation. These findings suggest our xeno‐free induction of forebrain OPCs from hPSCs could accelerate clinical translation for brain‐specific disorders.

show abstract

HuCNS-SC Human NSCs Fail to Differentiate, Form Ectopic Clusters, and Provide No Cognitive Benefits in a Transgenic Model of Alzheimer's Disease

Cited by 52 publications

References 45 publications

Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

Neural stem cell therapy for neurodegenerative disorders: The role of neurotrophic support

Xeno‐free culture for generation of forebrain oligodendrocyte precursor cells from human pluripotent stem cells

Contact Info

Product

Resources

About