Artificial extracellular matrix scaffolds of mobile molecules enhance maturation of human stem cell-derived neurons

Zaida Álvarez; J Alberto Ortega; Kohei Sato; Ivan R Sasselli; Alexandra N Kolberg-Edelbrock; Ruomeng Qiu; Kelly A Marshall; Thao Phuong Nguyen; Cara S Smith; Katharina A Quinlan; Vasileios Papakis; Zois Syrgiannis; Nicholas A Sather; Chiara Musumeci; Elisabeth Engel; Samuel I Stupp; Evangelos Kiskinis

doi:10.1016/j.stem.2022.12.010

Artificial extracellular matrix scaffolds of mobile molecules enhance maturation of human stem cell-derived neurons

Cell Stem Cell. 2023 Feb 2;30(2):219-238.e14. doi: 10.1016/j.stem.2022.12.010. Epub 2023 Jan 12.

Authors

Zaida Álvarez¹, J Alberto Ortega², Kohei Sato³, Ivan R Sasselli⁴, Alexandra N Kolberg-Edelbrock⁵, Ruomeng Qiu³, Kelly A Marshall⁶, Thao Phuong Nguyen⁷, Cara S Smith⁵, Katharina A Quinlan⁸, Vasileios Papakis⁶, Zois Syrgiannis³, Nicholas A Sather⁹, Chiara Musumeci¹⁰, Elisabeth Engel¹¹, Samuel I Stupp¹², Evangelos Kiskinis¹³

Affiliations

¹ Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA; Department of Medicine, Northwestern University, Chicago, IL 60611, USA; Biomaterials for Regenerative Therapies, Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain.
² The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona 08907, Spain.
³ Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA; Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.
⁴ Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA; Department of Chemistry, Northwestern University, Evanston, IL 60208, USA; Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Donostia-San Sebastián 20014, Spain.
⁵ Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA; Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA.
⁶ The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁷ The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA.
⁸ Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
⁹ Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA.
¹⁰ Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA.
¹¹ Biomaterials for Regenerative Therapies, Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain.
¹² Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA; Department of Chemistry, Northwestern University, Evanston, IL 60208, USA; Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA; Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA; Department of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: s-stupp@northwestern.edu.
¹³ Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA; The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: evangelos.kiskinis@northwestern.edu.

Abstract

Human induced pluripotent stem cell (hiPSC) technologies offer a unique resource for modeling neurological diseases. However, iPSC models are fraught with technical limitations including abnormal aggregation and inefficient maturation of differentiated neurons. These problems are in part due to the absence of synergistic cues of the native extracellular matrix (ECM). We report on the use of three artificial ECMs based on peptide amphiphile (PA) supramolecular nanofibers. All nanofibers display the laminin-derived IKVAV signal on their surface but differ in the nature of their non-bioactive domains. We find that nanofibers with greater intensity of internal supramolecular motion have enhanced bioactivity toward hiPSC-derived motor and cortical neurons. Proteomic, biochemical, and functional assays reveal that highly mobile PA scaffolds caused enhanced β1-integrin pathway activation, reduced aggregation, increased arborization, and matured electrophysiological activity of neurons. Our work highlights the importance of designing biomimetic ECMs to study the development, function, and dysfunction of human neurons.

Keywords: IKVAV; dynamics; extracellular matrix; iPSC-derived neurons; laminin; neuronal maturation; peptide amphiphiles; supramolecular motion; supramolecular nanofibers.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Extracellular Matrix / metabolism
Humans
Induced Pluripotent Stem Cells*
Nanofibers* / chemistry
Neurons / metabolism
Proteomics

Abstract

Publication types

MeSH terms

Grants and funding