Functional Assessment of Local versus Systemic Adipose-derived Stromal Cell Therapy in Rodent Peripheral Nerve Regeneration

Stefan Targosinski^1*Nadine Wieser²Holger Jan Klein^1,3Pranitha Kamat¹André Alexander Barth¹Elisabeth Jane Rushing⁴Bong-Sung Kim¹Jan A. Plock^1,3Riccardo Schweizer^1,5

• ¹Department of Plastic Surgery and Hand Surgery, University Hospital Zürich, Zurich, Switzerland
• ²Faculty of Medicine, University of Zurich, Zurich, Switzerland
• ³Department of Plastic Surgery and Hand Surgery, Cantonal Hospital Aarau, Aarau, Switzerland
• ⁴Institute of Neuropathology, University Hospital Zürich, Zurich, Switzerland
• ⁵Department of Hand Surgery and Plastic Surgery, Cantonal Hospital Lucerne, Lucerne, Switzerland

Introduction: Adipose-derived stromal cell (ASC)–based therapies may play an important role in peripheral nerve regeneration, though the optimal route of application remains unclear. Systemically injected ASCs have been recognized to home to sites of inflammation and injury but also facilitate a widespread regenerative effect throughout the body. The advantage of local ASC administration is the direct and concentrated application at the site of need. Here, we investigated the effect of local versus systemic ASCs on functional recovery in a rodent sciatic nerve injury model. Methods: Twenty Lewis rats underwent sciatic transection and repair with a 10 mm nerve autograft and were subsequently assigned into three groups based on the ASC-treatment: systemic (SYS; n=8), local (LOC; n=8) and no ASCs (CTRL; n=4). ASCs (1×10^6) were administered i.v. (SYS) or locally at the nerve repair site (LOC). Functional outcome was assessed by a swim test and static sciatic index (SSI) preoperatively and weekly until endpoint (week 14). Gastrocnemius muscle weight ratio and nerve-specific histomorphometry were examined at the endpoint. Results: The swim test analyses noticed the nerve lesion and assessed functional recovery. Horizontal hindlimb excursion improved slightly and showed earlier recovery in the SYS group compared to LOC at week 6 (p < 0.05). The maximum ankle angle increased steadily until the endpoint in the ASC groups, but did not show relevant improvement in controls (CTRL 94.8±10.4° vs. SYS 118.2±19.1°; p<0.001 and LOC 109.8±7.1°; p<0.05). The swim toe spread index (SwTS) and SSI demonstrated recovery from week 6, with superior sensitivity of the SwTS in differentiating between the groups and improved function after systemic administration (CTRL vs. SYS p<0.05). ASCs were able to reduce gastrocnemius muscle atrophy (LOC 0.66±0.04 vs. SYS 0.56±0.18; p=0.18 and vs. CTRL 0.44±0.2; p<0.05). Histomorphometry confirmed axonal remyelination. Conclusion: Current ASC treatments modestly enhance functional recovery and reduce muscular atrophy after peripheral nerve injury. A slight trend toward better therapeutic effect was observed with systemic administration, although the differences remained small compared to local application. Ideal dosage, optimal timepoint as well as combination of local and systemic ASC-therapies need further assessment.