A group from the University of Pennsylvania used SIS stem cells derived from gingival tissue to treat transected facial nerve and sciatic nerve crush injuries in rats

Peripheral nerve injuries are a common challenge in clinical practice that can result in permanent disability due to the rapid loss of the myelin sheath and axonal integrity following traumatic crush injuries.¹ Current interventions are limited in their ability to stimulate regeneration and functional recovery of severe injuries, lending to the need for better treatment options. It is known that Schwann cells and macrophages in the local injury microenvironment play critical roles in nerve repair and regeneration following injury, so one promising treatment strategy may focus on a means to manipulate the plastic phenotype of the macrophage into the pro-regenerative (M2) phenotype and away from the pro-inflammatory (M1) phenotype. The use of immunomodulatory biomaterials and mesenchymal stem cells, both of which have been shown to promote M2 macrophage polarization, may be one way to accomplish this goal.^2,3

A group of researchers at the University of Pennsylvania School of Dental Medicine isolated GMSC and cultured them in a 3-dimensional (3D)-collagen hydrogel which converted the GMSC to Schwann cell precursors (now referred to as GiSC) as measured by surface markers and mRNA expression.⁴ The team then filled nerve protector tubes made from a decellularized small intestinal submucosa (SIS) extracellular matrix (ECM) with GMSC encapsulated in 3D collagen hydrogels.¹ Constructs were cultured in the lab for 24 hours to allow for the conversion of GMSC into GISCs and the generation of functionalized nerve protectors, with GISCs transmigrating into the SIS. Protectors were then implanted as either a bridge across a 6-mm gap of the buccal branch of the facial nerves4 or as a wraparound protector of crushed sciatic nerves1 in rat models. Nerves were evaluated using functional and histological assessments.

Both models showed that the functionalized nerve protectors repopulated with GiSCs significantly accelerated functional recovery and axonal regeneration. Furthermore, assessments of macrophage phenotype at the explant site demonstrated an increased pro-regenerative (M2) response and a decreased infiltration of M1 pro-inflammatory macrophages. These findings suggest that Schwann-like cells converted from GMSCs represent a promising source of supportive cells for regenerative therapy of peripheral nerve injuries, and that tubes made from SIS can help retain the cells at the site of injury for as long as 14 weeks.⁴

¹ Zhang Q, Burrell JC, Zeng J, et al. Implantation of a nerve protector embedded with human GMSC-derived Schwann-like cells accelerates regeneration of crush-injured rat sciatic nerves. Stem Cell Res Ther. 2022;13(1):263.

² Li X, Guan Y, Li C, et al. Immunomodulatory effects of mesenchymal stem cells in peripheral nerve injury. Stem Cell Res Ther. 2022;13(1):18.

³ Zhukauskas R, Fischer DN, Deister C, Alsmadi NZ, Mercer D. A Comparative study of porcine small intestine submucosa and cross-linked bovine type I collagen as a nerve conduit. J Hand Surg Glob Online. 2021;3(5):282–288.

⁴ Zhang Q, Nguyen P, Burrell JC, et al. Harnessing 3D collagen hydrogel-directed conversion of human GMSCs into SCP-like cells to generate functionalized nerve conduits. NPJ Regen Med. 2021;6:59.