The Effects of the Combination of Mesenchymal Stromal Cells and Nanofiber-Hydrogel Composite on Repair of the Contused Spinal Cord.

A bone marrow-derived mesenchymal stromal cell (MSC) transplant and a bioengineered nanofiber-hydrogel composite (NHC) have been shown to stimulate nervous tissue repair in the contused spinal cord in rodent models. Here, these two modalities were combined to assess their repair effects in the contused spinal cord in adult rats. Cohorts of contused rats were treated with MSC in NHC (MSC-NHC), MSC in phosphate-buffered saline (MSC-PBS), NHC, or PBS injected into the contusion site at 3 days post-injury. One week after injury, there were significantly fewer CD68+ cells in the contusion with MSC-NHC and NHC, but not MSC-PBS. The reduction in CD86+ cells in the injury site with MSC-NHC was mainly attributed to NHC. One and eight weeks after injury, we found a greater CD206+/CD86+ cell ratio with MSC-NHC or NHC, but not MSC-PBS, indicating a shift from a pro-inflammatory towards an anti-inflammatory milieu in the injury site. Eight weeks after injury, the injury size was significantly reduced with MSC-NHC, NHC, and MSC-PBS. At this time, astrocyte, and axon presence in the injury site was greater with MSC-NHC compared with MSC-PBS. We did not find a significant effect of NHC on MSC transplant survival, and hind limb function was similar across all groups. However, we did find fewer macrophages at 1 week post-injury, more macrophages polarized towards a pro-regenerative phenotype at 1 and 8 weeks after injury, and reduced injury volume, more astrocytes, and more axons at 8 weeks after injury in rats with MSC-NHC and NHC alone compared with MSC-PBS; these findings were especially significant between rats with MSC-NHC and MSC-PBS. The data support further study in the use of an NHC-MSC combination transplant in the contused spinal cord.

The Effect of Inflammatory Priming on the Therapeutic Potential of Mesenchymal Stromal Cells for Spinal Cord Repair.

Mesenchymal stromal cells (MSC) are used for cell therapy for spinal cord injury (SCI) because of their ability to support tissue repair by paracrine signaling. Preclinical and clinical research testing MSC transplants for SCI have revealed limited success, which warrants the exploration of strategies to improve their therapeutic efficacy. MSC are sensitive to the microenvironment and their secretome can be altered in vitro by exposure to different culture media. Priming MSC with inflammatory stimuli increases the expression and secretion of reparative molecules. We studied the effect of macrophage-derived inflammation priming on MSC transplants and of primed MSC (pMSC) acute transplants (3 days) on spinal cord repair using an adult rat model of moderate-severe contusive SCI. We found a decrease in long-term survival of pMSC transplants compared with unprimed MSC transplants. With a pMSC transplant, we found significantly more anti-inflammatory macrophages in the contusion at 4 weeks post transplantation (wpt). Blood vessel presence and maturation in the contusion at 1 wpt was similar in rats that received pMSC or untreated MSC. Nervous tissue sparing and functional recovery were similar across groups. Our results indicate that macrophage-derived inflammation priming does not increase the overall therapeutic potential of an MSC transplant in the adult rat contused spinal cord.

Macrophage-Derived Inflammation Induces a Transcriptome Makeover in Mesenchymal Stromal Cells Enhancing Their Potential for Tissue Repair.

Pre-clinical and clinical studies revealed that mesenchymal stromal cell (MSC) transplants elicit tissue repair. Conditioning MSC prior to transplantation may boost their ability to support repair. We investigated macrophage-derived inflammation as a means to condition MSC by comprehensively analyzing their transcriptome and secretome. Conditioning MSC with macrophage-derived inflammation resulted in 3208 differentially expressed genes, which were annotated with significantly enriched GO terms for 1085 biological processes, 85 cellular components, and 79 molecular functions. Inflammation-mediated conditioning increased the secretion of growth factors that are key for tissue repair, including vascular endothelial growth factor, hepatocyte growth factor, nerve growth factor and glial-derived neurotrophic factor. Furthermore, we found that inflammation-mediated conditioning induces transcriptomic changes that challenge the viability and mobility of MSC. Our data support the notion that macrophage-derived inflammation stimulates MSC to augment their paracrine repair-supporting activity. The results suggest that inflammatory pre-conditioning enhances the therapeutic potential of MSC transplants.

Mesenchymal Stem Cell-Macrophage Choreography Supporting Spinal Cord Repair.

Spinal cord injury results in destructive events that lead to tissue loss and functional impairments. A hallmark of spinal cord injury is the robust and persistent presence of inflammatory macrophages. Mesenchymal stem cells (MSCs) are known to benefit repair of the damaged spinal cord often associated with improved functional recovery. Transplanted MSCs immediately encounter the abundance of inflammatory macrophages in the injury site. It is known that MSCs interact closely and reciprocally with macrophages during tissue healing. Here, we will review the roles of (transplanted) MSCs and macrophages in spinal cord injury and repair. Molecular interactions between MSCs and macrophages and the deficiencies in our knowledge about the underlying mechanisms will be reviewed. We will discuss possible ways to benefit from the MSC-macrophage choreography for developing repair strategies for the spinal cord.

Biomaterials for revascularization and immunomodulation after spinal cord injury.

Spinal cord injury (SCI) causes immediate damage to the nervous tissue accompanied by loss of motor and sensory function. The limited self-repair competence of injured nervous tissue underscores the need for reparative interventions to recover function after SCI. The vasculature of the spinal cord plays a crucial role in SCI and repair. Ruptured and sheared blood vessels in the injury epicenter and blood vessels with a breached blood-spinal cord barrier (BSCB) in the surrounding tissue cause bleeding and inflammation, which contribute to the overall tissue damage. The insufficient formation of new functional vasculature in and near the injury impedes endogenous tissue repair and limits the prospect of repair approaches. Limiting the loss of blood vessels, stabilizing the BSCB, and promoting the formation of new blood vessels are therapeutic targets for spinal cord repair. Inflammation is an integral part of injury-mediated vascular damage, which has deleterious and reparative consequences. Inflammation and the formation of new blood vessels are intricately interwoven. Biomaterials can be effectively used for promoting and guiding blood vessel formation or modulating the inflammatory response after SCI, thereby governing the extent of damage and the success of reparative interventions. This review deals with the vasculature after SCI, the reciprocal interactions between inflammation and blood vessel formation, and the potential of biomaterials to support revascularization and immunomodulation in damaged spinal cord nervous tissue.