Bone Marrow Stem Cells and Polymer Hydrogels—Two Strategies for Spinal Cord Injury Repair

Abstract

1. Emerging clinical studies of treating brain and spinal cord injury (SCI) led us to examine the effect of autologous adult stem cell transplantation as well as the use of polymer scaffolds in spinal cord regeneration. We compared an intravenous injection of mesenchymal stem cells (MSCs) or the injection of a freshly prepared mononuclear fraction of bone marrow cells (BMCs) on the treatment of an acute or chronic balloon-induced spinal cord compression lesion in rats. Based on our experimental studies, autologous BMC implantation has been used in a Phase I/II clinical trial in patients (n=20) with a transversal spinal cord lesion. 2. MSCs were isolated from rat bone marrow by their adherence to plastic, labeled with iron-oxide nanoparticles and expanded in vitro. Macroporous hydrogels based on derivatives of 2-hydroxyethyl methacrylate (HEMA) or 2-hydroxypropyl methacrylamide (HPMA) were prepared, then modified by their copolymerization with a hydrolytically degradable crosslinker, N,O-dimethacryloylhydroxylamine, or by different surface electric charges. Hydrogels or hydrogels seeded with MSCs were implanted into rats with hemisected spinal cords. 3. Lesioned animals grafted with MSCs or BMCs had smaller lesions 35 days postgrafting and higher scores in BBB testing than did control animals and also showed a faster recovery of sensitivity in their hind limbs using the plantar test. The functional improvement was more pronounced in MSC-treated rats. In MR images, the lesion populated by grafted cells appeared as a dark hypointense area and was considerably smaller than in control animals. Morphometric measurements showed an increase in the volume of spared white matter in cell-treated animals. In the clinical trial, we compared intraarterial (via a. vertebralis, n=6) versus intravenous administration of BMCs (n=14) in a group of subacute (10-33 days post-SCI, n=8) and chronic patients (2-18 months, n=12). For patient follow-up we used MEP, SEP, MRI, and the ASIA score. Our clinical study revealed that the implantation of BMCs into patients is safe, as there were no complications following cell administration. Partial improvement in the ASIA score and partial recovery of MEP or SEP have been observed in all subacute patients who received cells via a. vertebralis (n=4) and in one out of four subacute patients who received cells intravenously. Improvement was also found in one chronic patient who received cells via a. vertebralis. A much larger population of patients is needed before any conclusions can be drawn. The implantation of hydrogels into hemisected rat spinal cords showed that cellular ingrowth was most pronounced in copolymers of HEMA with a positive surface electric charge. Although most of the cells had the morphological properties of connective tissue elements, we found NF-160-positive axons invading all the implanted hydrogels from both the proximal and distal stumps. The biodegradable hydrogels degraded from the border that was in direct contact with the spinal cord tissue. They were resorbed by macr...

Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury

“…transplantation into a rat model of spinal cord injury. 93 Transplanted cells survived without immunosuppression and resulted in functional recovery at 3 and 4 weeks. Human MSCs, like those of rodents, secrete neurotrophic factors and cytokines, and can enhance functional recovery after transplantation into the injured spinal cord despite very few cells remaining after 11 weeks.…”

“…There is one other published report about additional current clinical trials of MSCs in humans with spinal cord injury, but no definite results have appeared. 93 There are several other unpublished trials underway (personal communication, reviewed in Tator). 6 …”

Migration, fate and in vivo imaging of adult stem cells in the CNS

“…injection of Endorem-labeled non-hematopoietic rat MSCs. 55,56 The results obtained were compared with those following the implantation of a freshly isolated mononuclear fraction of bone marrow containing stromal cells, hematopoietic and non-hematopoietic stem and precursor cells and lymphocytes (BMCs), and with those following the injection of granulocyte colony-stimulating factor (G-CSF). G-CSF is a growth factor that mobilizes endogenous BMCs containing mainly hematopoietic stem cells, but also progenitor cells and lymphocytes.…”

Poly (hydroxyethyl methacrylate-glycidyl methacrylate) films modified with different functional groups: In vitro interactions with platelets and rat stem cells

“…Thus, MSCs emerge as an important player of cellular-based therapies and new approaches are required to increase the viability and functionality of MSCs. For post-polymer surface modifications, reactive co-monomers, typically containing epoxy groups are generally used for single step post polymerization techniques [12,17,18].…”