Early Intravenous Delivery of Human Brain Stromal Cells Modulates Systemic Inflammation and Leads to Vasoprotection in Traumatic Spinal Cord Injury

Abstract

Central nervous system pericytes (perivascular stromal cells) have recently gained significant attention within the scientific community. In addition to being recognized as major players in neurotrauma, pericytes have been discovered to share a common origin and potentially function with traditionally defined mesenchymal stromal cells (MSCs). Although there have been several in vitro comparisons, the in vivo therapeutic application of human brain-derived stromal cells has not been previously evaluated. This study demonstrates that these cells not only display a MSC phenotype in vitro but also have similar in vivo immunomodulatory effects after spinal cord injury that are more potent than those of non-central nervous system tissue-derived cells. Therefore, these cells are of great interest for therapeutic use in spinal cord injury.

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

“…Our findings here mirror our recent study with human brain-derived vascular pericytes, whereby an acute infusion was able to mitigate acute neurovascular readouts and result in chronic functional improvement after traumatic cervical SCI [88]. In this study, we find that this effect is not exclusive to brain-derived pericytes, but also extends to umbilical cordderived MSCs.…”

“…The most effective cell administration route for the integration of donor cells within and near the lesion site is still debated, even though the invasiveness of intraparenchymal cell injection is well recognized, in addition to the challenge this poses to the application of cell therapy, especially during the acute phase of injury. However, the benefits of intravenous cell administration are clear from this study as well as others . Although not yet a fully validated therapy for SCI, the safety of this approach has already been established through preclinical SCI studies , its clinical application to other conditions affecting the CNS, including multiple sclerosis and bone marrow transplantations.…”

“…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 Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

“…Early intravenous delivery of MSC attenuates injury by regulating inflammation in SCI [43] and traumatic brain injury (TBI) [44][45][46]. Additionally, MSC transplantation can reduce the levels of proinflammatory cytokines, such as TNF-α and IL-1 [11,47], and inhibit NFκB signaling [12,48,49].…”

Induced Pluripotent Stem Cells for Traumatic Spinal Cord Injury

“…Recently, our lab has shown that human fetal cadaveric perivascular stromal cells (pericytes) derived from the central nervous system (CNS-PSCs) have unique immunoregulatory functions that can reduce peripheral inflammatory cell infiltration and the permeability of the blood-spinal cord barrier after early intravenous injection (Badner et al, 2016). The disadvantage of CNS-PSCs is that they are not easily accessible and have a limited capacity to proliferate which limits their therapeutic efficacy.…”