Splenic involvement in umbilical cord matrix-derived mesenchymal stromal cell-mediated effects following traumatic spinal cord injury

Abstract

BackgroundThe spleen plays an important role in erythrocyte turnover, adaptive immunity, antibody production, and the mobilization of monocytes/macrophages (Mφ) following tissue injury. In response to trauma, the spleen initiates production of inflammatory cytokines, which in turn recruit immune cells to the inflamed tissue, exacerbating damage. Our previous work has shown that intravenous mesenchymal stromal cell (MSC) infusion has potent immunomodulatory effects following spinal cord injury (SCI), associated with the transplanted cells homing to and persisting within the spleen. Therefore, this work aimed to characterize the relationship between the splenic inflammatory response and SCI pathophysiology, emphasizing splenic involvement in MSC-mediated effects.MethodsUsing a rodent model of cervical clip-compression SCI, secondary tissue damage and functional recovery were compared between splenectomised rodents and those with a sham procedure. Subsequently, 2.5 million MSCs from the term human umbilical cord matrix cells (HUCMCs) were infused via tail vein at 1-h post-SCI and the effects were assessed in the presence or absence of a spleen.ResultsSplenectomy alone had no effect on lesion volume, hemorrhage, or inflammation. There was also no significant difference between the groups in functional recovery and those in lesion morphometry. Yet, while the infusion of HUCMCs reduced spinal cord hemorrhage and increased systemic levels of IL-10 in the presence of a spleen, these effects were lost with splenectomy. Further, HUCMC infusion was shown to alter the expression levels of splenic cytokines, suggesting that the spleen is an important target and site of MSC effects.ConclusionsOur results provide a link between MSC function and splenic inflammation, a finding that can help tailor the cells/transplantation approach to enhance therapeutic efficacy.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1243-0) contains supplementary material, which is available to authorized users.

Axon Degeneration Is Rescued with Human Umbilical Cord Perivascular Cells: A Potential Candidate for Neuroprotection After Traumatic Brain Injury

“…The fact that conditioned media derived from HUCPVCs did not rescue degeneration in OGD cultures suggests that an injury cue is required to produce factors that promote axon survival. This notion is supported by our in vivo findings whereby HUCPVCs improved cortical axon morphology despite evidence indicating that many MSCs get trapped in peripheral organs, such as the lung, liver, and spleen [8,54,55]. At 24 h, although not quantified, we found the systemically injected PKH26-labeled cells in the lungs and spleen but not in the brain.…”

Early Intravenous Infusion of Mesenchymal Stromal Cells Exerts a Tissue Source Age-Dependent Beneficial Effect on Neurovascular Integrity and Neurobehavioral Recovery After Traumatic Cervical Spinal Cord Injury

“…However, we were unable to find any transplanted cells at the lesional and peri‐lesional area. Strikingly, our lab and others have recently reported that, while systemically infused MSCs distribute mainly to the lung and spleen, they continue to exert therapeutic effects on the local spinal cord milieu. In these studies, the authors propose two possible mechanisms through which the remotely distributed MSCs exert their therapeutic effect: (a) MSCs serve as cellular decoys, where the immune system targets these exogeneous human cells instead of endogenous cells, thus minimizing damage; and (b) MSCs release anti‐inflammatory cytokines in the spleen, such as IL10, and impact immune cell recruitment and phenotype.…”

Mesenchymal stromal cells lower platelet activation and assist in platelet formation in vitro

“…Previous studies have identified MSC-like cells in human UC tissue, but the cells were not well defined (16)(17)(18)(19)(20)(21). Unlike previously isolated UC tissue stromal cells, which have been primarily derived from Wharton's jelly (17)(18)(19)21), we focused on isolating arterial-derived stromal cells since perivascular cells around arteries have been shown to regulate hematopoietic cell production during development (24). Using flow cytometry, we found a population of CD51 + PDGFRα + arterial-derived stromal cells, termed cord-tissue Mesenchymal Stromal Cells (cMSCs), which were nonerythroid (CD235a -), nonendothelial (CD31 -), and nonhematopoietic (CD45 -).…”

“…Since cord blood-derived CD34 cells have been shown to differentiate into megakaryocytes with high efficiency compared with those isolated from peripheral blood and BM, we focused on identifying a compatible stromal cell from human UC tissue (23). Previous studies have identified MSC-like cells in human UC tissue, but the cells were not well defined (16)(17)(18)(19)(20)(21). Unlike previously isolated UC tissue stromal cells, which have been primarily derived from Wharton's jelly (17)(18)(19)21), we focused on isolating arterial-derived stromal cells since perivascular cells around arteries have been shown to regulate hematopoietic cell production during development (24).…”

“…Previously, it was shown that human BM MSCs (bMSCs), defined by their adherence to tissue culture plates, can improve platelet formation in vitro, although the nature of the cells was not well defined (15). Human umbilical cord (UC) tissue, has also been shown to harbor MSCs, although these cells have not been thoroughly characterized (16)(17)(18)(19)(20)(21).…”