Culture on 3D Chitosan-Hyaluronic Acid Scaffolds Enhances Stem Cell Marker Expression and Drug Resistance in Human Glioblastoma Cancer Stem Cells

Kui Wang, Forrest M. Kievit, Ariane E. Erickson, John R. Silber, Richard G. Ellenbogen, Miqin Zhang

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The lack of in vitro models that support the growth of glioblastoma (GBM) stem cells (GSCs) that underlie clinical aggressiveness hinders developing new, effective therapies for GBM. While orthotopic patient-derived xenograft models of GBM best reflect in vivo tumor behavior, establishing xenografts is a time consuming, costly, and frequently unsuccessful endeavor. To address these limitations, a 3D porous scaffold composed of chitosan and hyaluronic acid (CHA) is synthesized. Growth and expression of the cancer stem cell (CSC) phenotype of the GSC GBM6 taken directly from fresh xenogratfs grown on scaffolds or as adherent monolayers is compared. While 2D adherent cultures grow as monolayers of flat epitheliod cells, GBM6 cells proliferate within pores of CHA scaffolds as clusters of self-adherent ovoid cells. Growth on scaffolds is accompanied by greater expression of genes that mediate epithelial–mesenchymal transition and maintain a primitive, undifferentiated phenotype, hallmarks of CSCs. Scaffold-grown cells also display higher expression of genes that promote resistance to hypoxia-induced oxidative stress. In accord, scaffold-grown cells show markedly greater resistance to clinically utilized alkylating agents compared to adherent cells. These findings suggest that our CHA scaffolds better mimic in vivo biological and clinical behavior and provide insights for developing novel individualized treatments.

Original languageEnglish (US)
Pages (from-to)3173-3181
Number of pages9
JournalAdvanced Healthcare Materials
Volume5
Issue number24
DOIs
StatePublished - Dec 21 2016

Fingerprint

Hyaluronic acid
Neoplastic Stem Cells
Chitosan
Hyaluronic Acid
Scaffolds (biology)
Glioblastoma
Stem cells
Cell culture
Drug Resistance
Scaffolds
Stem Cells
Pharmaceutical Preparations
Heterografts
Monolayers
Growth
Genes
Phenotype
Gene Expression
Oxidative stress
Alkylating Agents

Keywords

  • chitosan
  • drug resistance
  • glioblastoma stem cell
  • hyaluronic acid
  • scaffold

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering
  • Pharmaceutical Science

Cite this

Culture on 3D Chitosan-Hyaluronic Acid Scaffolds Enhances Stem Cell Marker Expression and Drug Resistance in Human Glioblastoma Cancer Stem Cells. / Wang, Kui; Kievit, Forrest M.; Erickson, Ariane E.; Silber, John R.; Ellenbogen, Richard G.; Zhang, Miqin.

In: Advanced Healthcare Materials, Vol. 5, No. 24, 21.12.2016, p. 3173-3181.

Research output: Contribution to journalArticle

Wang, Kui ; Kievit, Forrest M. ; Erickson, Ariane E. ; Silber, John R. ; Ellenbogen, Richard G. ; Zhang, Miqin. / Culture on 3D Chitosan-Hyaluronic Acid Scaffolds Enhances Stem Cell Marker Expression and Drug Resistance in Human Glioblastoma Cancer Stem Cells. In: Advanced Healthcare Materials. 2016 ; Vol. 5, No. 24. pp. 3173-3181.
@article{91c33e5e03f441d7afc6b16c795c8d63,
title = "Culture on 3D Chitosan-Hyaluronic Acid Scaffolds Enhances Stem Cell Marker Expression and Drug Resistance in Human Glioblastoma Cancer Stem Cells",
abstract = "The lack of in vitro models that support the growth of glioblastoma (GBM) stem cells (GSCs) that underlie clinical aggressiveness hinders developing new, effective therapies for GBM. While orthotopic patient-derived xenograft models of GBM best reflect in vivo tumor behavior, establishing xenografts is a time consuming, costly, and frequently unsuccessful endeavor. To address these limitations, a 3D porous scaffold composed of chitosan and hyaluronic acid (CHA) is synthesized. Growth and expression of the cancer stem cell (CSC) phenotype of the GSC GBM6 taken directly from fresh xenogratfs grown on scaffolds or as adherent monolayers is compared. While 2D adherent cultures grow as monolayers of flat epitheliod cells, GBM6 cells proliferate within pores of CHA scaffolds as clusters of self-adherent ovoid cells. Growth on scaffolds is accompanied by greater expression of genes that mediate epithelial–mesenchymal transition and maintain a primitive, undifferentiated phenotype, hallmarks of CSCs. Scaffold-grown cells also display higher expression of genes that promote resistance to hypoxia-induced oxidative stress. In accord, scaffold-grown cells show markedly greater resistance to clinically utilized alkylating agents compared to adherent cells. These findings suggest that our CHA scaffolds better mimic in vivo biological and clinical behavior and provide insights for developing novel individualized treatments.",
keywords = "chitosan, drug resistance, glioblastoma stem cell, hyaluronic acid, scaffold",
author = "Kui Wang and Kievit, {Forrest M.} and Erickson, {Ariane E.} and Silber, {John R.} and Ellenbogen, {Richard G.} and Miqin Zhang",
year = "2016",
month = "12",
day = "21",
doi = "10.1002/adhm.201600684",
language = "English (US)",
volume = "5",
pages = "3173--3181",
journal = "Advanced healthcare materials",
issn = "2192-2640",
publisher = "John Wiley and Sons Ltd",
number = "24",

}

TY - JOUR

T1 - Culture on 3D Chitosan-Hyaluronic Acid Scaffolds Enhances Stem Cell Marker Expression and Drug Resistance in Human Glioblastoma Cancer Stem Cells

AU - Wang, Kui

AU - Kievit, Forrest M.

AU - Erickson, Ariane E.

AU - Silber, John R.

AU - Ellenbogen, Richard G.

AU - Zhang, Miqin

PY - 2016/12/21

Y1 - 2016/12/21

N2 - The lack of in vitro models that support the growth of glioblastoma (GBM) stem cells (GSCs) that underlie clinical aggressiveness hinders developing new, effective therapies for GBM. While orthotopic patient-derived xenograft models of GBM best reflect in vivo tumor behavior, establishing xenografts is a time consuming, costly, and frequently unsuccessful endeavor. To address these limitations, a 3D porous scaffold composed of chitosan and hyaluronic acid (CHA) is synthesized. Growth and expression of the cancer stem cell (CSC) phenotype of the GSC GBM6 taken directly from fresh xenogratfs grown on scaffolds or as adherent monolayers is compared. While 2D adherent cultures grow as monolayers of flat epitheliod cells, GBM6 cells proliferate within pores of CHA scaffolds as clusters of self-adherent ovoid cells. Growth on scaffolds is accompanied by greater expression of genes that mediate epithelial–mesenchymal transition and maintain a primitive, undifferentiated phenotype, hallmarks of CSCs. Scaffold-grown cells also display higher expression of genes that promote resistance to hypoxia-induced oxidative stress. In accord, scaffold-grown cells show markedly greater resistance to clinically utilized alkylating agents compared to adherent cells. These findings suggest that our CHA scaffolds better mimic in vivo biological and clinical behavior and provide insights for developing novel individualized treatments.

AB - The lack of in vitro models that support the growth of glioblastoma (GBM) stem cells (GSCs) that underlie clinical aggressiveness hinders developing new, effective therapies for GBM. While orthotopic patient-derived xenograft models of GBM best reflect in vivo tumor behavior, establishing xenografts is a time consuming, costly, and frequently unsuccessful endeavor. To address these limitations, a 3D porous scaffold composed of chitosan and hyaluronic acid (CHA) is synthesized. Growth and expression of the cancer stem cell (CSC) phenotype of the GSC GBM6 taken directly from fresh xenogratfs grown on scaffolds or as adherent monolayers is compared. While 2D adherent cultures grow as monolayers of flat epitheliod cells, GBM6 cells proliferate within pores of CHA scaffolds as clusters of self-adherent ovoid cells. Growth on scaffolds is accompanied by greater expression of genes that mediate epithelial–mesenchymal transition and maintain a primitive, undifferentiated phenotype, hallmarks of CSCs. Scaffold-grown cells also display higher expression of genes that promote resistance to hypoxia-induced oxidative stress. In accord, scaffold-grown cells show markedly greater resistance to clinically utilized alkylating agents compared to adherent cells. These findings suggest that our CHA scaffolds better mimic in vivo biological and clinical behavior and provide insights for developing novel individualized treatments.

KW - chitosan

KW - drug resistance

KW - glioblastoma stem cell

KW - hyaluronic acid

KW - scaffold

UR - http://www.scopus.com/inward/record.url?scp=84995890866&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84995890866&partnerID=8YFLogxK

U2 - 10.1002/adhm.201600684

DO - 10.1002/adhm.201600684

M3 - Article

C2 - 27805789

AN - SCOPUS:84995890866

VL - 5

SP - 3173

EP - 3181

JO - Advanced healthcare materials

JF - Advanced healthcare materials

SN - 2192-2640

IS - 24

ER -