UCLA researchers in the Department of Bioengineering have developed an innovative cell-based therapy addressing the recovery from denervation atrophy by intramuscularly delivering neural crest stem cells in various constructs.
BACKGROUND:
Muscular denervation atrophy of various etiologies can result in weakness or loss of functional independence, as well as respiratory failure and mortality. Conventional therapies focus on reinnervation at the site of the damage. However, if the target muscle atrophies in the interim, it may be unreceptive to reinnervation, and the regain of function will be hindered. Cell-based therapies, with the potential for paracrine signaling and tissue integration, has advantages over synthetic manipulation of complex, incompletely-understood regenerative processes in improving the functional outcomes for neuromuscular regeneration. The bottleneck of current stem cell therapies is the low survival rate of transplanted cells.
INNOVATION:
UCLA researchers in the Department of Bioengineering have developed a novel cell-based therapy to address the recovery from denervation atrophy. The therapy encompasses neural crest stem cells (NCSCs) and relevant derivatives or precursors. Cell constructs can range in size from single-digit numbers of cells to thousands of cells, and can be injected intramuscularly into the affected muscle. The formation of spheroids improves the survival rate of transplanted cells. In vivo data assessing intramuscular iPSC-NCSC transplantation shows improvement of muscle wet weight, neuromuscular junctions, electrophysiology and functional recovery as early as four weeks after injury and injection.
POTENTIAL APPLICATIONS:
• Denervation atrophy therapies
• Reinnervation
• Other muscular atrophies
ADVANTAGES:
• The novel cell selection of NCSCs and/or progenitors/derivatives thereof poses singular advantages in both being the natural precursors of the peripheral nervous system as well as playing key roles in early muscle formation and progenitor maintenance, enabling more physiological relevance than other cellular therapeutics with the possibility of both paracrine signaling as well as cell integration.
• NCSC spheroids significantly improve cell survival and functions. The high-throughput fabrication of cell constructs will enable more effective stem cell therapy. Size, composition, and quantity of constructs can be optimized for cell survival and desired therapeutic function
• The engineering of ultra-thin biomaterial encapsulation of multi-cellular constructs, such as with 3D-printed devices, will enable easy scale-up for potential future large-scale clinical use, which can also be generalized for other applications involving cell encapsulation. The material composition and dimensions are optimized for the application.
DEVELOPMENT-TO-DATE:
In vivo proof-of-concept on a rat sciatic nerve transection model of peripheral nerve injury has shown improved muscle wet weight, neuromuscular junctions, electrophysiology and functional recovery as early as four weeks after injury and injection.
RELATED PAPERS:
Li, LK, Huang, WC, Ding, X, Hsueh, YY, Li, S. Engineering stem cell spheroids to rescue muscular denervation atrophy. Poster presentation at Micro- and Nanotechnologies in Medicine Symposium, Los Angeles, CA, Jul 2018.
Huang C-W, Huang W-C, Qiu X, Fernandes Ferreira da Silva F, Wang A, Patel S, Nesti LJ, Poo M-M, Li S. The Differentiation Stage of Transplanted Stem Cells Modulates Nerve Regeneration. Sci Rep. 2017.