Rehabilitation enhances functional recovery after intravenous infusion of mesenchymal stem cells for chronic cerebral ischemia in rats

Tatsuro Yamashita, Masanori Sasaki, Yuichi Sasaki, Hiroshi Nagahama, Shinichi Oka, Yuko Kataoka-Sasaki, Takahiro Yokoyama, Masato Kobayashi, Ryo Ukai, Masafumi Kakizawa, Osamu Honmou
Purpose:

The synergistic effects of combining a rehabilitation strategy (daily treadmill exercise) with intravenous infusion of MSCs were investigated in a rat model of chronic cerebral ischemia.The synergistic effects of combining a rehabilitation strategy (daily treadmill exercise) with intravenous infusion of MSCs were investigated in a rat model of chronic cerebral ischemia.

Methods:

Permanent middle cerebral artery occlusion (MCAO) was induced in Sprague-Dawley rats. Eight weeks after MCAO induction, the rats were used as a chronic cerebral ischemia model. Four experimental groups were studied: Vehicle group (medium only, no cells), Rehab group (vehicle + rehabilitation), MSC group (MSC only), and Combined group (MSC + rehabilitation). Rat MSCs were intravenously infused eight weeks after MCAO induction, and the MCAO rats received daily rehabilitation through treadmill exercise for 20 min. Behavioral testing (Treadmill stress test, Limb Placement Test and modified Neurological Severity Scores), lesion volume assessment using magnetic resonance imaging (MRI), and histological analysis were performed during the observation period until 16 weeks after MCAO induction.

Results:

All treated animals showed functional improvement compared with the Vehicle group; however, the therapeutic efficacy was greatest in the Combined group. The combination therapy is associated with enhanced neural plasticity, as shown by histological analysis and MRI diffusion tensor imaging. Furthermore, we examined the relationship between motor function (maximum speed on the treadmill test) at 16 weeks and two anatomical conditions–the number of DTI tracks and CC thickness–and found a positive correlation, suggesting that these relationships contribute to improved motor function. This study also confirmed a positive correlation between the number of DTI tracks and CC thickness (as determined by Nissl staining) supporting the interrelationship of these anatomical changes.

Conclusion(s):

The study results indicate that combined therapy consisting of MSC therapy and rehabilitation therapy has a positive effect on behavioral performance and structural changes in the CC during the chronic phase of cerebral ischemia. The combination therapy resulted in the most significant behavioral improvement, the thickest CC, and increased connectivity of the neural tracts.

Implications:

These findings provide behavioral evidence for enhanced recovery by combined therapy with rehabilitation and intravenous infusion of MSCs and potentially forming the basis for future clinical protocols.

Funding acknowledgements:
This work was supported by JSPS KAKENHI grant (grant number 21K11194)
Keywords:
chronic stroke
mesenchymal stem cells
rehabilitation
Primary topic:
Basic science including molecular and cellular health
Did this work require ethics approval?:
Yes
Name the institution and ethics committee that approved your work:
The Animal Care and Use Committee of Sapporo Medical University
Provide the ethics approval number:
#21-094_22-082
Has any of this material been/due to be published or presented at another national or international conference prior to the World Physiotherapy Congress 2025?:
Yes

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