Concurrent Delivery of Soluble and Immobilized Proteins
to Recruit and Differentiate Neural Stem Cells
Posted on 2019-08-27 - 21:43
Insufficient
endogenous neural stem cell (NSC) migration to injury
sites and incomplete replenishment of neurons complicates recovery
following central nervous system (CNS) injury. Such insufficient migration
can be addressed by delivering soluble chemotactic factors, such as
stromal cell-derived factor 1-α (SDF-1α), to sites of
injury. However, simply enhancing NSC migration is likely to result
in insufficient regeneration, as the cells need to be given additional
signals. Immobilized proteins, such as interferon-γ (IFN-γ)
can encourage neurogenic differentiation of NSCs. Here, we combined
both protein delivery paradigms: soluble SDF-1α delivery to
enhance NSC migration alongside covalently tethered IFN-γ to
differentiate the recruited NSCs into neurons. To slow the release
of soluble SDF-1α, we copolymerized methacrylated heparin with
methacrylamide chitosan (MAC), to which we tethered IFN-γ. We
found that this hydrogel system could result in soft hydrogels with
a ratio of up to 70:30 MAC/heparin by mass, which enabled the continuous
release of SDF-1α over a period of 2 weeks. The hydrogels recruited
NSCs in vitro over 2 weeks, proportional to their release rate: the
70:30 heparin gels recruited a consistent number of NSCs at each time
point, while the formulations with less heparin recruited NSCs at
only early time points. After remaining in contact with the hydrogels
for 8 days, NSCs successfully differentiated into neurons. CNS regeneration
is a complex challenge, and this system provides a foundation to address
multiple aspects of that challenge.
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Ham, Trevor
R.; Cox, Dakotah G.; Leipzig, Nic D. (2019). Concurrent Delivery of Soluble and Immobilized Proteins
to Recruit and Differentiate Neural Stem Cells. ACS Publications. Collection. https://doi.org/10.1021/acs.biomac.9b00719