Combination of Adult Mesenchymal Stem Cell Therapy and Immunomodulation with Dimethyl Fumarate Following Spinal Cord Ventral Root Repair

Autor(es)

Gelinski Kempe, Paula Regina ; de Castro, Mateus Vidigal ; Coser, Lilian de Oliveira ; Cartarozzi, Luciana Politti ; Barraviera, Benedito ; Ferreira Jr, Rui Seabra ; de Oliveira, Alexandre Leite Rodrigues

• Tipo de documento: Artigo Científico
• Fonte: BIOLOGY-BASEL; v. 13, n. 11, p. 18-pg., 2024-11-01.

Resumo

Spinal cord injury affects millions of individuals worldwide, underscoring the urgent need for more effective treatments that can facilitate the recovery of motor and sensory functions. The use of neuroprotective molecules in conjunction with stem cell therapy may facilitate the restoration of function, thereby enabling patients to resume a productive lifestyle. The present study demonstrates that the combination of dimethyl fumarate, an immunomodulatory drug, with adult mesenchymal stem cells derived from adipose tissue exhibits neuroprotective and immunomodulatory properties. Furthermore, we observed a notable rescue of spinal motoneurons following the avulsion and reimplantation of ventral roots. Additionally, glial reactions were reduced, which may contribute to enhanced long-term outcomes. The collective findings support the potential of integrated regenerative strategies following spinal cord root injury. Spinal cord injury results in significant motor and sensory loss. In the experimental ventral root avulsion (VRA) model, the ventral (motor) roots are disconnected from the spinal cord surface, disrupting contact between spinal motoneurons and muscle fibers. Axotomized motoneurons typically degenerate within two to three weeks after avulsion, the situation being exacerbated by an increased glial response and chronic inflammation. Nevertheless, root reimplantation has been observed to stimulate regenerative potential in some motoneurons, serving as a model for CNS/PNS regeneration. We hypothesized that a combination of neuroprotective and immunomodulatory therapies is capable of enhancing regenerative responses following nerve root injury and repair. A heterologous fibrin biopolymer (HFB) was used for surgical repair; dimethyl fumarate (DMF) was used for neuroprotection and immunomodulation; and adipose tissue-derived mesenchymal stem cells (AT-MSCs) were used as a source of trophic factors and cytokines that may further enhance neuronal survival. Thus, adult female Lewis rats underwent unilateral VRA of the L4-L6 roots, followed by reimplantation with HFB, AT-MSCs transplantation, and daily DMF treatment for four weeks, with a 12-week postoperative survival period. An evaluation of the results focused on light microscopy, qRT-PCR, and the Catwalk motor function recovery system. Data were analyzed using one-way or two-way ANOVA (p < 0.05). The results indicate that the combined therapy resulted in a reduced glial response and a 70% improvement in behavioral motor recovery. Overall, the data support the potential of combined regenerative approaches after spinal cord root injury. (AU)

• Processo FAPESP: 18/05006-0 - Recuperação sensório-motora após axotomia de raízes medulares: emprego de diferentes abordagens experimentais
• Beneficiário: Alexandre Leite Rodrigues de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 21/11936-3 - Centro de Ciência Translacional e Desenvolvimento de Biofármacos
• Beneficiário: Benedito Barraviera
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Ciência para o Desenvolvimento
• Processo FAPESP: 18/25845-7 - Efeito neuroprotetor e imunomodulatório do dimetil-fumarato (DMF) após avulsão e reimplante de raízes motoras medulares associados à terapia celular
• Beneficiário: Paula Regina Gelinski Kempe
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto