Generation of RRMS and PPMS specific iPSCs as a platform for modeling Multiple Sclerosis

Mutukula, Naresh; Man, Zhiqiu; Takahashi, Yuta; Martinez, F; Morales, Mariana Fouilloux; Carreón-Guarnizo, Ester; Clares, Rocio Hernandez; García‐Bernal, David; Martinez, Llanos Martinez; Lajara, Jerónimo; Núñez-Delicado, Estrella; Lallana, José Eustasio Meca; Belmonte, Juan Carlos Izpisúa

doi:10.1016/j.scr.2021.102319

Cited by 15 publications

(17 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In control, RRMS and SPMS samples no/very low number of p16INK4A + cells were detected while majority of cells in PPMS sample were expression this marker. This increase of senescence in PPMS NPCs compared to control and RRMS NPCs has previously been observed (Nicaise et al, 2019; Mutukula et al, 2021), highlighting cellular senescence in PPMS NPCs.…”

Section: Resultssupporting

confidence: 81%

Cerebral Organoids In Primary Progressive Multiple Sclerosis Reveal Stem Cell Disruption And Failure To Produce Oligodendrocytes

Daviaud

Chen

Edwards

et al. 2022

Preprint

View full text Add to dashboard Cite

Multiple sclerosis (MS) is an auto-immune inflammatory disorder affecting the central nervous system. The cause of the disease is unknown but both genetic and environmental factors are implicated in the pathogenesis. We derived cerebral organoids from induced pluripotent stem cells (iPSC) of healthy control subjects as well as from primary progressive MS (PPMS), secondary progressive MS (SPMS) and relapsing remitting MS (RRMS) patients to better understand the pathologic basis of the varied clinical phenotypic expressions of MS. In MS organoids, most notably in PPMS, we observed a decrease of proliferation marker Ki67 and a reduction of the SOX2+ stem cell pool associated with an increased expression of neuronal markers CTIP2 and TBR1. This dysregulation of the stem cell pool is associated with a decreased expression of the cell cycle inhibitor p21. Our findings show that the genetic background of a patient can directly alter stem cell function. This study also provides new insights on the innate cellular dysregulation in MS and identifies p21 pathway as a new potential target for therapeutic strategies in MS.

show abstract

Section: Resultssupporting

confidence: 81%

Cerebral Organoids In Primary Progressive Multiple Sclerosis Reveal Stem Cell Disruption And Failure To Produce Oligodendrocytes

Daviaud

Chen

Edwards

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Previous work in our lab determined that induced pluripotent stem cells (iPSCs) obtained from primary progressive MS (PPMS) patients and subsequently differentiated to NPCs were deficient in supporting myelin regeneration both in vitro and in vivo when compared to iPS-derived NPCs from age matched controls (Nicaise et al, 2017 ). It was initially reported, and recently independently confirmed by others (Mutukula et al, 2021 ), that NPCs from PPMS samples in vitro exhibit a senescent phenotype, and validated the finding that Sox2+ progenitor cells in progressive MS brain tissues expressed elevated levels of cellular p16, p21, p53, and other markers (Nicaise et al, 2019 ). This finding indicated that the conditioned media (CM) from iPS-derived NPCs from PPMS patients represents a disease-associated senescent secretory phenotype.…”

Section: Introductionmentioning

confidence: 60%

The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination

Rouillard

Sutter

et al. 2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

HMGB1 is a highly conserved, ubiquitous protein in eukaryotic cells. HMGB1 is normally localized to the nucleus, where it acts as a chromatin associated non-histone binding protein. In contrast, extracellular HMGB1 is an alarmin released by stressed cells to act as a danger associated molecular pattern (DAMP). We have recently determined that progenitor cells from multiple sclerosis patients exhibit a cellular senescent phenotype and release extracellular HMGB1 which directly impaired the maturation of oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes (OLs). Herein, we report that administration of recombinant HMGB1 into the spinal cord at the time of lysolecithin administration resulted in arrest of OPC differentiation in vivo, and a profound impairment of remyelination. To define the receptor by which extracellular HMGB1 mediates its inhibitory influence on OPCs to impair OL differentiation, we tested selective inhibitors against the four primary receptors known to mediate the effects of HMGB1, the toll-like receptors (TLRs)-2, -4, -9 or the receptor for advanced glycation end-products (RAGE). We found that inhibition of neither TLR9 nor RAGE increased OL differentiation in the presence of HMGB1, while inhibition of TLR4 resulted in partial restoration of OL differentiation and inhibiting TLR2 fully restored differentiation of OLs in the presence of HMGB1. Analysis of transcriptomic data (RNAseq) from OPCs identified an overrepresentation of NFκB regulated genes in OPCs when in the presence of HMGB1. We found that application of HMGB1 to OPCs in culture resulted in a rapid and concentration dependent shift in NFκB nuclear translocation which was also attenuated with coincident TLR2 inhibition. These data provide new information on how extracellular HMGB1 directly affects the differentiation potential of OPCs. Recent and past evidence for elevated HMGB1 released from senescent progenitor cells within demyelinated lesions in the MS brain suggests that a greater understanding of how this molecule acts on OPCs may unfetter the endogenous remyelination potential in MS.

show abstract

“…The iPSCs derived from patients presented reduced PAX6 expression, associated with difficulty differentiating to subsequent lineages. These cells also showed more marked cellular senescence, a process involved in pathological cellular stress and inflammation [51]. Given the involvement of these two processes in demyelination in MS, it is essential to seek to better understand these results, as they may lead the way to new therapies based on the modulation of cellular senescence.…”

Section: Induced Pluripotent Stem Cellsmentioning

confidence: 99%

The Integration of Cell Therapy and Biomaterials as Treatment Strategies for Remyelination

López-Muguruza

Villar-Gómez

Matías‐Guiu

et al. 2022

Life

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a chronic degenerative autoimmune disease of the central nervous system that causes inflammation, demyelinating lesions, and axonal damage and is associated with a high rate of early-onset disability. Disease-modifying therapies are used to mitigate the inflammatory process in MS but do not promote regeneration or remyelination; cell therapy may play an important role in these processes, modulating inflammation and promoting the repopulation of oligodendrocytes, which are responsible for myelin repair. The development of genetic engineering has led to the emergence of stable, biocompatible biomaterials that may promote a favorable environment for exogenous cells. This review summarizes the available evidence about the effects of transplantation of different types of stem cells reported in studies with several animal models of MS and clinical trials in human patients. We also address the advantages of combining cell therapy with biomaterials.

show abstract

Generation of RRMS and PPMS specific iPSCs as a platform for modeling Multiple Sclerosis

Cited by 15 publications

References 49 publications

Cerebral Organoids In Primary Progressive Multiple Sclerosis Reveal Stem Cell Disruption And Failure To Produce Oligodendrocytes

Cerebral Organoids In Primary Progressive Multiple Sclerosis Reveal Stem Cell Disruption And Failure To Produce Oligodendrocytes

The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination

The Integration of Cell Therapy and Biomaterials as Treatment Strategies for Remyelination

Contact Info

Product

Resources

About