Peripheral nerve injury, especially critical-sized nerve gap injury, often results in poor recovery of function and
impaired quality of life for the patient. Stem cell therapy holds significant promise; however, its clinical application
has been largely hampered by limited stem cell adhesion and the lack of efficient differentiation. We have shown
that our stem cell surface modification technique is able to profoundly influence specific cell-cell and cell-matrix
interactions. Therefore, our specific aims are to develop and optimize novel candidate analogs to promote human
adipose stem cell (hASC) adhesion and differentiation in vitro; to incorporate the cell surface modification
technique into hASC-based therapies to improve peripheral nerve regeneration; and to investigate related
mechanisms underlying improved nerve regeneration.
Aim1: To develop and optimize novel analogs by metabolic glycoengineering (MGE) technology to
promote hASC's cell adhesion and cell differentiation in vitro. We will optimize the cell surface modification with
thiolated sugar analogs (ManNAc), evaluate the effects, and thoroughly characterize them to promote hASCs
adhesion, proliferation, and differentiation.
Aim2: To incorporate MGE into hASC-based therapies to improve peripheral nerve regeneration. With
optimized ManNAc analogs, we will systemically evaluate the effect of glycoengineered hASCs on nerve
regeneration after nerve repair and further optimize the therapy.
the mechanism by which thiol-derivatized ManNAc analogs contribute to nerve
With expected improvements in nerve regeneration,
we will evaluate signaling pathways (e.g., Wnt
ß after MGE'ed hASC transplantation.
-catenin) modulated by MGE
The innovation lies in our hypothesis to modify stem cell surface glycan properties with sugar analogs to
improve cell survival and differentiation, our novel and effective technology, and the new application of these
technologies in a fully translational nerve repair model to develop a novel treatment. The significance lies in the
novel cell-based therapy with surface modification to address one of the most challenging aspects of nerve
regeneration for critical-sized nerve gap repair, and the expected discovery of the mechanism underlying
improved survival and differentiation by transplanted MGE'ed hASC. Our technology and protocols are highly
translatable to the clinical environment. Success in this project will have direct translational implications for
patients with peripheral nerve trauma requiring surgical repair. The clinical study of ManNAc has demonstrated
the safety of single oral doses up to 6 g, and the FDA has approved the use of ManNAc to treat GNE Myopathy.
Our study will lead to the development of novel therapeutic strategies for nerve repair that can contribute to
future clinical interventions and maximize the benefits of stem cell therapy based on the new findings.