Heparan sulfate regulates the fate decisions of human pluripotent stem cells
Heparan sulfate (HS) is an anionic polysaccharide generated by all animal cells, but our understanding of its roles in human pluripotent stem cell (hPSC) self-renewal and differentiation is limited. We derived HS-deficient hPSCs by disrupting the EXT1 glycosyltransferase. These EXT1<sup>-/-</sup> hPSCs maintain self-renewal and pluripotency under standard culture conditions that contain high levels of basic fibroblast growth factor(bFGF), a requirement for sufficient bFGF signaling in the engineered cells. Intriguingly, Activin/Nodal signaling is also compromised in EXT1<sup>-/-</sup> hPSCs, highlighting HS's previously unexplored involvement in this pathway. As a result, EXT1<sup>-/-</sup> hPSCs fail to differentiate into mesoderm or endoderm lineages. Unexpectedly, HS is dispensable for early ectodermal differentiation of hPSCs but still critical in generating motor neurons. Those derived from HS-deficient hPSCs lack proper neuronal projections and show alterations in axonogenesis gene expression. Thus, our study uncovers expected and unexpected mechanistic roles of HS in hPSC fate decisions.
Authors
- Ke Xia (ORCID: https://orcid.org/0000-0001-9699-9901)
- Yilan Ouyang (ORCID: https://orcid.org/0000-0001-5373-310X)
- Yefim Zaltsman (ORCID: https://orcid.org/0000-0002-2979-8197)
- Deena Al Mahbuba (ORCID: https://orcid.org/0000-0003-1951-6165)
- Sayaka Masuko (ORCID: https://orcid.org/0000-0002-9072-0356)
- Andrew C. Elton (ORCID: https://orcid.org/0000-0003-4388-5227)
- Robert J. Linhardt
- Deepsing Syangtan (ORCID: https://orcid.org/0000-0001-5245-4782)
- Fuming Zhang (ORCID: https://orcid.org/0000-0003-2803-3704)
- Paul J. Wrighton (ORCID: https://orcid.org/0000-0002-0354-0278)
- Laura L. Kiessling (ORCID: https://orcid.org/0000-0001-6829-1500)
- Xiaorui Han (ORCID: https://orcid.org/0000-0001-9510-4838)
- Qiao Li
Institutions
- University of Wisconsin–Madison (US)
- Rensselaer Polytechnic Institute (US)
- IIT@MIT (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Stem Cell Reports
- Published
- 2024-12-26
- DOI
- https://doi.org/10.1016/j.stemcr.2024.11.014
- Citations
- 3
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- Open Philanthropy Project
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- Good Ventures Foundation
- National Institutes of Health
- National Institute of General Medical Sciences