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

Author(s)

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

• Document type: Journal article
• Source: BIOLOGY-BASEL; v. 13, n. 11, p. 18-pg., 2024-11-01.

Abstract

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)

• FAPESP's process: 18/05006-0 - Sensorimotor recovery following spinal root axotomy: use of different experimental approaches
• Grantee: Alexandre Leite Rodrigues de Oliveira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/11936-3 - Center for Translational Science and Biopharmaceutical Development
• Grantee: Benedito Barraviera
• Support Opportunities: Research Grants - Science Centers for Development
• FAPESP's process: 18/25845-7 - Neuroprotective and immunomodulatory effect of dimethyl-fumarate (DMF) after avulsion and reimplantation of spinal motor roots associated to cell-therapy
• Grantee: Paula Regina Gelinski Kempe
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)