Spatially Self-Organized Three-Dimensional Neural Concentroid as a Novel Reductionist Humanized Model to Study Neurovascular Development

Yoke Chin Chai; San Kit To; Susan Simorgh; Samantha Zaunz; YingLi Zhu; Karan Ahuja; Alix Lemaitre; Roya Ramezankhani; Bernard K van der Veer; Keimpe Wierda; Stefaan Verhulst; Leo A van Grunsven; Vincent Pasque; Catherine Verfaillie

doi:10.1002/advs.202304421

Spatially Self-Organized Three-Dimensional Neural Concentroid as a Novel Reductionist Humanized Model to Study Neurovascular Development

Yoke Chin Chai, San Kit To, Susan Simorgh, Samantha Zaunz, YingLi Zhu, Karan Ahuja, Alix Lemaitre, Roya Ramezankhani, Bernard K van der Veer, Keimpe Wierda, Stefaan Verhulst, Leo A van Grunsven, Vincent Pasque, Catherine Verfaillie

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Abstract

Although human pluripotent stem cell (PSC)-derived brain organoids have enabled researchers to gain insight into human brain development and disease, these organoids contain solely ectodermal cells and are not vascularized as occurs during brain development. Here it is created less complex and more homogenous large neural constructs starting from PSC-derived neuroprogenitor cells (NPC), by fusing small NPC spheroids into so-called concentroids. Such concentroids consisted of a pro-angiogenic core, containing neuronal and outer radial glia cells, surrounded by an astroglia-dense outer layer. Incorporating PSC-derived endothelial cells (EC) around and/or in the concentroids promoted vascularization, accompanied by differential outgrowth and differentiation of neuronal and astroglia cells, as well as the development of ectodermal-derived pericyte-like mural cells co-localizing with EC networks. Single nucleus transcriptomic analysis revealed an enhanced neural cell subtype maturation and diversity in EC-containing concentroids, which better resemble the fetal human brain compared to classical organoids or NPC-only concentroids. This PSC-derived "vascularized" concentroid brain model will facilitate the study of neurovascular/blood-brain barrier development, neural cell migration, and the development of effective in vitro vascularization strategies of brain mimics.

Original language	English
Article number	e2304421
Number of pages	20
Journal	Advanced Science
Volume	11
Issue number	5
Early online date	30 Nov 2023
DOIs	https://doi.org/10.1002/advs.202304421
Publication status	Published - Feb 2024

Bibliographical note

Funding Information:
The authors thank F.L Vinas and T. Tricot for editing the manuscript, and E. Van Schoor for performing the NeuN immunostaining. C.V., Y.C.C., S.S., R.R., S.Z., and K.A. were supported by the Research Foundation – Flanders (FWO) (FWO‐SBO‐S001221N‐OrganID, FWO‐G0B5819N), the Belgium Alzheimer's Research Foundation (SAO‐#3M200141), the America Alzheimer's Association (AARG‐NTF‐19‐616888), KUL C14/17/111 −3D‐MuSYC, and the Mitialto foundation. S.K.T., S.Z., K.A., and B.K.V. were funded by the FWO PhD fellowship [1S75720N (S.K.T), 11C3819N (S.Z), 1S03422N (K.A.), 11E7920N (B.K.V.)]. Y.Z. was supported by the Chinese Scholarship Council (CSC). Research in the Pasque laboratory was supported by the Research Foundation–Flanders (FWO; Odysseus Return Grant G0F7716N to V.P.; FWO grants G0C9320N and G0B4420N to V.P.), the KU Leuven Research Fund (C1 grant C14/21/19 to V.P.). The authors gratefully acknowledge the VIB Bio Imaging Core (LIMONE) for the access to the Nikon C2 confocal microscopy and their support and assistance in this work, and Thomas Pilkington from the Leuven FabLab on 3D printing of the micropillar array 24‐well plate system. The computational resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by FWO and the Flemish Government.

Publisher Copyright:
© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

Keywords

Blood-brain barrier
brain organoids
neurovascular
vascularization

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Advanced Science - 2023 - Chai - Spatially Self‐Organized Three‐Dimensional Neural Concentroid as a Novel ReductionistFinal published version, 8.57 MBLicence: CC BY

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Chai, Y. C., To, S. K., Simorgh, S., Zaunz, S., Zhu, Y., Ahuja, K., Lemaitre, A., Ramezankhani, R., van der Veer, B. K., Wierda, K., Verhulst, S., van Grunsven, L. A., Pasque, V., & Verfaillie, C. (2024). Spatially Self-Organized Three-Dimensional Neural Concentroid as a Novel Reductionist Humanized Model to Study Neurovascular Development. Advanced Science, 11(5), [e2304421]. https://doi.org/10.1002/advs.202304421

Chai, Yoke Chin ; To, San Kit ; Simorgh, Susan ; Zaunz, Samantha ; Zhu, YingLi ; Ahuja, Karan ; Lemaitre, Alix ; Ramezankhani, Roya ; van der Veer, Bernard K ; Wierda, Keimpe ; Verhulst, Stefaan ; van Grunsven, Leo A ; Pasque, Vincent ; Verfaillie, Catherine. / Spatially Self-Organized Three-Dimensional Neural Concentroid as a Novel Reductionist Humanized Model to Study Neurovascular Development. In: Advanced Science. 2024 ; Vol. 11, No. 5.

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abstract = "Although human pluripotent stem cell (PSC)-derived brain organoids have enabled researchers to gain insight into human brain development and disease, these organoids contain solely ectodermal cells and are not vascularized as occurs during brain development. Here it is created less complex and more homogenous large neural constructs starting from PSC-derived neuroprogenitor cells (NPC), by fusing small NPC spheroids into so-called concentroids. Such concentroids consisted of a pro-angiogenic core, containing neuronal and outer radial glia cells, surrounded by an astroglia-dense outer layer. Incorporating PSC-derived endothelial cells (EC) around and/or in the concentroids promoted vascularization, accompanied by differential outgrowth and differentiation of neuronal and astroglia cells, as well as the development of ectodermal-derived pericyte-like mural cells co-localizing with EC networks. Single nucleus transcriptomic analysis revealed an enhanced neural cell subtype maturation and diversity in EC-containing concentroids, which better resemble the fetal human brain compared to classical organoids or NPC-only concentroids. This PSC-derived {"}vascularized{"} concentroid brain model will facilitate the study of neurovascular/blood-brain barrier development, neural cell migration, and the development of effective in vitro vascularization strategies of brain mimics.",

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author = "Chai, {Yoke Chin} and To, {San Kit} and Susan Simorgh and Samantha Zaunz and YingLi Zhu and Karan Ahuja and Alix Lemaitre and Roya Ramezankhani and {van der Veer}, {Bernard K} and Keimpe Wierda and Stefaan Verhulst and {van Grunsven}, {Leo A} and Vincent Pasque and Catherine Verfaillie",

note = "Funding Information: The authors thank F.L Vinas and T. Tricot for editing the manuscript, and E. Van Schoor for performing the NeuN immunostaining. C.V., Y.C.C., S.S., R.R., S.Z., and K.A. were supported by the Research Foundation – Flanders (FWO) (FWO‐SBO‐S001221N‐OrganID, FWO‐G0B5819N), the Belgium Alzheimer's Research Foundation (SAO‐#3M200141), the America Alzheimer's Association (AARG‐NTF‐19‐616888), KUL C14/17/111 −3D‐MuSYC, and the Mitialto foundation. S.K.T., S.Z., K.A., and B.K.V. were funded by the FWO PhD fellowship [1S75720N (S.K.T), 11C3819N (S.Z), 1S03422N (K.A.), 11E7920N (B.K.V.)]. Y.Z. was supported by the Chinese Scholarship Council (CSC). Research in the Pasque laboratory was supported by the Research Foundation–Flanders (FWO; Odysseus Return Grant G0F7716N to V.P.; FWO grants G0C9320N and G0B4420N to V.P.), the KU Leuven Research Fund (C1 grant C14/21/19 to V.P.). The authors gratefully acknowledge the VIB Bio Imaging Core (LIMONE) for the access to the Nikon C2 confocal microscopy and their support and assistance in this work, and Thomas Pilkington from the Leuven FabLab on 3D printing of the micropillar array 24‐well plate system. The computational resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by FWO and the Flemish Government. Publisher Copyright: {\textcopyright} 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.",

year = "2024",

month = feb,

doi = "10.1002/advs.202304421",

language = "English",

volume = "11",

journal = "Advanced Science",

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Chai, YC, To, SK, Simorgh, S, Zaunz, S, Zhu, Y, Ahuja, K, Lemaitre, A, Ramezankhani, R, van der Veer, BK, Wierda, K, Verhulst, S , van Grunsven, LA, Pasque, V & Verfaillie, C 2024, 'Spatially Self-Organized Three-Dimensional Neural Concentroid as a Novel Reductionist Humanized Model to Study Neurovascular Development', Advanced Science, vol. 11, no. 5, e2304421. https://doi.org/10.1002/advs.202304421

Spatially Self-Organized Three-Dimensional Neural Concentroid as a Novel Reductionist Humanized Model to Study Neurovascular Development. / Chai, Yoke Chin; To, San Kit; Simorgh, Susan; Zaunz, Samantha; Zhu, YingLi; Ahuja, Karan; Lemaitre, Alix; Ramezankhani, Roya; van der Veer, Bernard K; Wierda, Keimpe; Verhulst, Stefaan ; van Grunsven, Leo A; Pasque, Vincent; Verfaillie, Catherine.

In: Advanced Science, Vol. 11, No. 5, e2304421, 02.2024.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Spatially Self-Organized Three-Dimensional Neural Concentroid as a Novel Reductionist Humanized Model to Study Neurovascular Development

AU - Chai, Yoke Chin

AU - To, San Kit

AU - Simorgh, Susan

AU - Zaunz, Samantha

AU - Zhu, YingLi

AU - Ahuja, Karan

AU - Lemaitre, Alix

AU - Ramezankhani, Roya

AU - van der Veer, Bernard K

AU - Wierda, Keimpe

AU - Verhulst, Stefaan

AU - van Grunsven, Leo A

AU - Pasque, Vincent

AU - Verfaillie, Catherine

N1 - Funding Information: The authors thank F.L Vinas and T. Tricot for editing the manuscript, and E. Van Schoor for performing the NeuN immunostaining. C.V., Y.C.C., S.S., R.R., S.Z., and K.A. were supported by the Research Foundation – Flanders (FWO) (FWO‐SBO‐S001221N‐OrganID, FWO‐G0B5819N), the Belgium Alzheimer's Research Foundation (SAO‐#3M200141), the America Alzheimer's Association (AARG‐NTF‐19‐616888), KUL C14/17/111 −3D‐MuSYC, and the Mitialto foundation. S.K.T., S.Z., K.A., and B.K.V. were funded by the FWO PhD fellowship [1S75720N (S.K.T), 11C3819N (S.Z), 1S03422N (K.A.), 11E7920N (B.K.V.)]. Y.Z. was supported by the Chinese Scholarship Council (CSC). Research in the Pasque laboratory was supported by the Research Foundation–Flanders (FWO; Odysseus Return Grant G0F7716N to V.P.; FWO grants G0C9320N and G0B4420N to V.P.), the KU Leuven Research Fund (C1 grant C14/21/19 to V.P.). The authors gratefully acknowledge the VIB Bio Imaging Core (LIMONE) for the access to the Nikon C2 confocal microscopy and their support and assistance in this work, and Thomas Pilkington from the Leuven FabLab on 3D printing of the micropillar array 24‐well plate system. The computational resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by FWO and the Flemish Government. Publisher Copyright: © 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

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Y1 - 2024/2

N2 - Although human pluripotent stem cell (PSC)-derived brain organoids have enabled researchers to gain insight into human brain development and disease, these organoids contain solely ectodermal cells and are not vascularized as occurs during brain development. Here it is created less complex and more homogenous large neural constructs starting from PSC-derived neuroprogenitor cells (NPC), by fusing small NPC spheroids into so-called concentroids. Such concentroids consisted of a pro-angiogenic core, containing neuronal and outer radial glia cells, surrounded by an astroglia-dense outer layer. Incorporating PSC-derived endothelial cells (EC) around and/or in the concentroids promoted vascularization, accompanied by differential outgrowth and differentiation of neuronal and astroglia cells, as well as the development of ectodermal-derived pericyte-like mural cells co-localizing with EC networks. Single nucleus transcriptomic analysis revealed an enhanced neural cell subtype maturation and diversity in EC-containing concentroids, which better resemble the fetal human brain compared to classical organoids or NPC-only concentroids. This PSC-derived "vascularized" concentroid brain model will facilitate the study of neurovascular/blood-brain barrier development, neural cell migration, and the development of effective in vitro vascularization strategies of brain mimics.

AB - Although human pluripotent stem cell (PSC)-derived brain organoids have enabled researchers to gain insight into human brain development and disease, these organoids contain solely ectodermal cells and are not vascularized as occurs during brain development. Here it is created less complex and more homogenous large neural constructs starting from PSC-derived neuroprogenitor cells (NPC), by fusing small NPC spheroids into so-called concentroids. Such concentroids consisted of a pro-angiogenic core, containing neuronal and outer radial glia cells, surrounded by an astroglia-dense outer layer. Incorporating PSC-derived endothelial cells (EC) around and/or in the concentroids promoted vascularization, accompanied by differential outgrowth and differentiation of neuronal and astroglia cells, as well as the development of ectodermal-derived pericyte-like mural cells co-localizing with EC networks. Single nucleus transcriptomic analysis revealed an enhanced neural cell subtype maturation and diversity in EC-containing concentroids, which better resemble the fetal human brain compared to classical organoids or NPC-only concentroids. This PSC-derived "vascularized" concentroid brain model will facilitate the study of neurovascular/blood-brain barrier development, neural cell migration, and the development of effective in vitro vascularization strategies of brain mimics.

KW - Blood-brain barrier

KW - brain organoids

KW - neurovascular

KW - vascularization

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DO - 10.1002/advs.202304421

M3 - Article

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VL - 11

JO - Advanced Science

JF - Advanced Science

SN - 2198-3844

IS - 5

M1 - e2304421

ER -

Spatially Self-Organized Three-Dimensional Neural Concentroid as a Novel Reductionist Humanized Model to Study Neurovascular Development

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