Functional recovery effects of growth factor-stimulated mesenchymal stromal cells in a Wistar rat model of ankle sprain injury

Background: Ankle sprain is among the most frequent musculoskeletal injuries affecting the anterior talofibular ligament (ATFL). Current management emphasizes symptom relief rather than regeneration, often resulting in prolonged recovery and recurrent instability. Wharton’s Jelly-derived mesenchymal stromal cells (WJ-MSCs) have emerged as promising candidates for ligament repair, particularly when primed with growth factors such as insulin-like growth factor-1 (IGF-1) and connective tissue growth factor (CTGF). Methods: A two-phase study was conducted. In vitro, WJ-MSCs were stimulated with IGF-1, CTGF, or sequential IGF-1/CTGF, and assessed for MSC marker expression, collagen gene transcription, and protein secretion. In vivo, grade II ATFL sprain was surgically induced in Wistar rats (n = 36), followed by local administration of growth factor-stimulated WJ-MSCs. Functional recovery was evaluated via swelling, locomotor activity, spontaneous rearing, and gait analysis. Histological assessment of ankle joints and major organs was performed on post-operative day (POD) 28. Results: Sequential IGF-1/CTGF stimulation synergistically enhanced Col1a1 expression (~ 8.2-fold vs. control, p < 0.001) and collagen I secretion (~ 19.5 ng/mL, p < 0.01). In vivo, MSCIGF+CTGF treatment accelerated oedema resolution, normalized gait symmetry by POD 6, and restored locomotor to near-baseline by POD 14. Histology revealed near-complete collagen alignment and minimal scarring in treated ankles, with no fibrotic changes in liver or brain and only mild transient pulmonary alterations. Conclusion: Sequential IGF-1/CTGF stimulation significantly augments the regenerative efficacy of WJ-MSCs, promoting structural restoration and multidimensional functional recovery in ligament injury. Local administration of dual-factor-programmed WJ-MSCs represents a safe and translationally relevant strategy for enhancing ATFL healing, with potential applicability to broader orthopaedic rehabilitation.

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