Human bone marrow-derived mesenchymal stem cell (BM-MSC) and neurosphere (BM-NS) transplantation as an adjunct to decompression in a rat degenerative cervical myelopathy (DCM) model

Abstract

Degenerative cervical myelopathy (DCM) is the most common form of degenerative cervical spinal cord disease in the developed world. Surgical decompression of the cervical spinal cord remains the most effective intervention. However, complete recovery after decompression is rare and evidence of non-operative treatments is lacking. Mesenchymal stem cell (MSC) and neural stem cell (NSC) therapies have been routinely tested in traumatic spinal cord injury but have yet to be tested in the context of DCM. MSC and NSC therapies have shown to aid neurological recovery in various central nervous system (CNS) disease contexts by trophic support and reconstituting the blood-CNS barrier. For the first time, human bone marrow-derived MSCs (BM-MSCs) and neurospheres (BM-NS) were investigated as an adjunct therapy to cervical decompression in an insertable polymer rat model of DCM.

100 male and female SD rats at age 10 - 15 weeks underwent five weeks of cervical compression by inserting a water-absorbant polyurethane polymer (L – 2mm, W – 1mm, H – 1mm) at the C4 epidural space. Decompression surgery (Day 0) was performed by removing the polymer, which required C4 laminectomy. 37 rats were used to observe locomotor function and blood-spinal cord barrier (BSCB) recovery during the 10-week post-decompression recovery period. 30 rats were used in a pilot batch to determine the safety, in vivo distribution and comparative efficacy of intravenous (IV) or intracisternal (CIS) injection of BM-MSCs delivered immediately after decompression. Lastly, 33 rats were used to assess the efficacy and in vivo engraftment of BM-MSC and BM-NS delivered intracisteranally 24-hours after decompression surgery (Day 1).

Dropout rate after compression and decompression surgery was 11% (surgical complication 3%, humane endpoint reached 8%). Functional recovery after decompression was delayed and limited with minor improvements in hindlimb and forelimb function by Week 10 and 8, respectively. BSCB disruption indicated by Evans Blue Dye (EBD) extravasation peaked at Week 4 and correlated with endoglin (CD105) expression. IV and CIS injection of BM-MSC was safe and well-tolerated but did not lead to significant improvement in locomotor function (p = 0.101, Rotarod Test: PBS vs CIS) or BSCB reconstitution by Day 10 post-decompression. In vivo cell tracing with luciferase showed significant peripheral organ entrapment of IV BM-MSC, while CIS BM-MSC remained at the cervical region and the injection site. Both CIS BM-MSC and BM-NS failed to significantly improve locomotor function by Day 20 (p = 0.136, Rotarod Test: PBS vs BM-NS) and did not survive in vivo. In this present work BM-MSC and BM-NS demonstrated limited short-term therapeutic benefits as an adjunct therapy to cervical decompression. Further optimization of the disease model, cell dose and timing, and behavior recovery period may be required to demonstrate the potential efficacy of BM-MSC and BM-NS in DCM. (Word count: 442)