Differential Effects of Heparin and Hyaluronic Acid on Neural Patterning of Human Induced Pluripotent Stem Cells
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A lack of well-established animal models that can efficiently represent human brain pathology has led to the development of human induced pluripotent stem cell (hiPSC)-derived brain tissues. Brain organoids have enhanced our ability to understand the developing human brain and brain disorders (e.g., Schizophrenia, microcephaly), but the organoids still do not accurately recapitulate the anatomical organization of the human brain. Therefore, it is important to evaluate and optimize induction and signaling factors in order to engineer the next generation of brain organoids. In this study, the impact of hyaluronic acid (HA), a major brain extracellular matrix (ECM) component that interacts with cells through ligand-binding receptors, on the patterning of brain organoids from hiPSCs was evaluated. To mediate HA- binding capacity of signaling molecules, heparin was added in addition to HA or conjugated to HA to form hydrogels (with two different moduli). The neural cortical spheroids derived from hiPSCs were treated with either HA or heparin plus HA (Hep- HA) and were analyzed for ECM impacts on neural patterning. The results indicate that Hep-HA has a caudalizing effect on hiPSC-derived neural spheroids, in particular for stiff Hep-HA hydrogels. Wnt and Hippo/Yes-associated protein (YAP) signaling was modulated (using Wnt inhibitor IWP4 or actin disruption agent Cytochalasin D respectively) to understand the underlying mechanism. IWP4 and cytochalasin D promote forebrain identity. The results from this study should enhance the understanding of influence of biomimetic ECM factors for brain organoid generation.
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Hyaluronic acid and mixtures of hyaluronic acid and chitosan have been extensively used in the growth and construction of neural organoids.
“Similarly, hyaluronic acid and mixtures of hyaluronic acid and chitosan have been extensively used in the growth and construction of neural organoids111–116.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [116]
Functionalizing hyaluronic acid with heparin affects neuronal patterning; the addition of heparin favored differentiation of human progenitors into neurons with a hindbrain fate, whereas non-functionalized hyaluronic acid favored a forebrain fate.
“Bejoy and colleagues showed that functionalizing hyaluronic acid with heparin affects neuronal patterning; the addition of heparin favored differentiation of human progenitors into neurons with a hindbrain fate, whereas non-functionalized hyaluronic acid favored a forebrain fate.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [116]
The stiffness of the hybrid hyaluronic acid material is relevant to cell fate determination; lower elastic moduli, ca. 300 Pa, led to forebrain development, whereas higher elastic moduli, ca. 1000 Pa, led to hindbrain development.
“The authors also established that the stiffness of this hybrid material is relevant to cell fate determination; lower elastic moduli, ca. 300 Pa, led to forebrain development, whereas higher elastic moduli, ca. 1000 Pa, led to hindbrain development116.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [116]
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- Authors
- Bejoy, J., Wang, Z., Bijonowski, B., Yang, M., Ma, T., Sang, Q.-X., & Li, Y.
- Affiliations
- Florida State University (US)
- Corresponding author
- Li, Yan
- Venue
- ACS Biomaterials Science & Engineering
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-11-04
- Volume
- 4
- Issue
- 12
- Pages
- 4354-4366
- ISSN
- 2373-9878 (ISSN-L)
- PMC
- PMC6768405
- OpenAlex
- W2898784277
- Cited by
- 46
- References
- 67
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 3 · 2023: 12 · 2022: 6 · 2021: 7 · 2019: 6 · 2017: 1
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Biomaterials Science & Engineering (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R03NS102640)
- Division of Chemical, Bioengineering, Environmental, and Transport Systems (1652992)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- heparin, hyaluronic acid, human induced pluripotent stem cells, brain organoids, neural patterning, extracellular matrix, hydrogels, Wnt signaling, Hippo/YAP signaling, cytochalasin D, biomimetic scaffolds
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