Modeling iPSC-derived human neurofibroma-like tumors in mice uncovers the heterogeneity of Schwann cells within plexiform neurofibromas.
Adolescent
Adult
Animals
Biomarkers
/ metabolism
Cell Differentiation
Child
Female
Humans
Induced Pluripotent Stem Cells
/ pathology
Male
Mesoderm
/ pathology
Mice
Middle Aged
Models, Biological
Neural Crest
/ pathology
Neurofibroma, Plexiform
/ pathology
Schwann Cells
/ pathology
Sciatic Nerve
/ pathology
Spheroids, Cellular
/ pathology
Young Adult
RNA-seq
Schwann cell
engraftment
fibroblast
iPSC
neural crest
neurofibromatosis type 1
plexiformneurofibroma
scRNA-seq
spheroids
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
15 02 2022
15 02 2022
Historique:
received:
05
07
2021
revised:
04
11
2021
accepted:
24
01
2022
entrez:
16
2
2022
pubmed:
17
2
2022
medline:
3
3
2022
Statut:
ppublish
Résumé
Plexiform neurofibromas (pNFs) are developmental tumors that appear in neurofibromatosis type 1 individuals, constituting a major source of morbidity and potentially transforming into a highly metastatic sarcoma (MPNST). pNFs arise after NF1 inactivation in a cell of the neural crest (NC)-Schwann cell (SC) lineage. Here, we develop an iPSC-based NC-SC in vitro differentiation system and construct a lineage expression roadmap for the analysis of different 2D and 3D NF models. The best model consists of generating heterotypic spheroids (neurofibromaspheres) composed of iPSC-derived differentiating NF1(-/-) SCs and NF1(+/-) pNF-derived fibroblasts (Fbs). Neurofibromaspheres form by maintaining highly proliferative NF1(-/-) cells committed to the NC-SC axis due to SC-SC and SC-Fb interactions, resulting in SC linage cells at different maturation points. Upon engraftment on the mouse sciatic nerve, neurofibromaspheres consistently generate human NF-like tumors. Analysis of expression roadmap genes in human pNF single-cell RNA-seq data uncovers the presence of SC subpopulations at distinct differentiation states.
Identifiants
pubmed: 35172160
pii: S2211-1247(22)00106-1
doi: 10.1016/j.celrep.2022.110385
pii:
doi:
Substances chimiques
Biomarkers
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
110385Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.