Extracellular Vesicles Can Deliver Anti-inflammatory and Anti-scarring Activities of Mesenchymal Stromal Cells After Spinal Cord Injury

Romanelli, Pasquale; Bieler, Lara; Scharler, Cornelia; Pachler, Karin; Kreutzer, Christina; Zaunmair, Pia; Jakubecova, Dominika; Mrowetz, Heike; Benedetti, Bruno; Rivera, Francisco J.; Aigner, Ludwig; Rohde, Eva; Gimona, Mario; Strunk, Dirk; Couillard‐Després, Sébastien

doi:10.3389/fneur.2019.01225

Cited by 68 publications

(70 citation statements)

References 45 publications

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“…The formation of fibrotic and glial scar is a major impediment to axonal regeneration after SCI. While reports with bmSC have claimed to reduce this [8,13,15], we did not see differences in scar formation or lesion size between different groups. Either there was a transient effect, not visible ten weeks after SCI, or the damage caused by a 200 Kdyn (2 N) contusion injury was simply too large to put any scar reducing effects in evidence.…”

Section: The Putative Mode Of Action Of Bmsc After Scicontrasting

confidence: 96%

“…To date, more than 25 studies have been published using bone marrow-derived stem cells to treat SCI in rats [8,15,25,26]. In the past, the cells were usually expanded before use and their phenotype was not characterized.…”

Section: Discussionmentioning

confidence: 99%

“…This raises the question regarding the mechanisms by which the injected bmSC were effective in our experiments. Increasing evidence suggests that extracellular vehicles (EVs) are important players in mediating the therapeutic effects of therapeutically applied stem cells [15,26,46,47]. Exosomes from mesenchymal stem cells exert immune-suppressive effects by enforcing M2 macrophage polarization, inhibiting complement activation [26] and indirectly driving regulatory T cell induction [14].…”

Section: The Putative Mode Of Action Of Bmsc After Scimentioning

confidence: 99%

“…As indicated (t-test * p < 0.05) treatment with MP was associated with reduced CD68-IR compared to saline treatment. Injections of bmSC had no significant effect paracrine factors can be effective, although repeated delivery may be required [15,46]. It is believed that beneficial effects of bmSC are derived rather from the mesenchymal and not the hematopoietic stem cell fraction [8], and this view is linked to the expectation that the cells integrate and differentiate in the tissue [49].…”

Section: The Putative Mode Of Action Of Bmsc After Scimentioning

confidence: 99%

“…With non-neuronal stem cells, on the other hand, the main rationale consists in modulating the inflammatory response [7,13]. Paracrine factors and extracellular vesicles that are released from mesenchymal stem cells are expected to prevent secondary degeneration and to support a regenerative remodeling after SCI [8,14,15]. An easily accessible source of this type of cells is the bone marrow, which contains hematopoietic and mesenchymal stem cells.…”

Section: Introductionmentioning

confidence: 99%

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Treatment of rats with spinal cord injury using human bone marrow-derived stromal cells prepared by negative selection

Romero‐Ramírez

Munter³

et al. 2020

J Biomed Sci

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Background: Spinal cord injury (SCI) is a highly debilitating pathology without curative treatment. One of the most promising disease modifying strategies consists in the implantation of stem cells to reduce inflammation and promote neural regeneration. In the present study we tested a new human bone marrow-derived stromal cell preparation (bmSC) as a therapy of SCI.Methods: Spinal cord contusion injury was induced in adult male rats at thoracic level T9/T10 using the Infinite Horizon impactor. One hour after lesion the animals were treated with a sub-occipital injection of human bmSC into the cisterna magna. No immune suppression was used. One dose of bmSC consisted, on average, of 2.3 million non-manipulated cells in 100 μL suspension, which was processed out of fresh human bone marrow from the iliac crest of healthy volunteers. Treatment efficacy was compared with intraperitoneal injections of methylprednisolone (MP) and saline. The recovery of motor functions was assessed during a surveillance period of nine weeks. Adverse events as well as general health, weight and urodynamic functions were monitored daily. After this time, the animals were perfused, and the spinal cord tissue was investigated histologically.Results: Rats treated with bmSC did not reject the human implants and showed no sign of sickness behavior or neuropathic pain. Compared to MP treatment, animals displayed better recovery of their SCI-induced motor deficits. There were no significant differences in the recovery of bladder control between groups. Histological analysis at ten weeks after SCI revealed no differences in tissue sparing and astrogliosis, however, bmSC treatment was accompanied with reduced axonal degeneration in the dorsal ascending fiber tracts, lower Iba1-immunoreactivity (IR) close to the lesion site and reduced apoptosis in the ventral grey matter. Neuroinflammation, as evidenced by CD68-IR, was significantly reduced in the MP-treated group.Conclusions: Human bmSC that were prepared by negative selection without expansion in culture have neuroprotective properties after SCI. Given the effect size on motor function, implantation in the acute phase was not sufficient to induce spinal cord repair. Due to their immune modulatory properties, allogeneic implants of bmSC can be used in combinatorial therapies of SCI.

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Section: The Putative Mode Of Action Of Bmsc After Scicontrasting

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: The Putative Mode Of Action Of Bmsc After Scimentioning

confidence: 99%

Section: The Putative Mode Of Action Of Bmsc After Scimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Treatment of rats with spinal cord injury using human bone marrow-derived stromal cells prepared by negative selection

Romero‐Ramírez

Munter³

et al. 2020

J Biomed Sci

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Extracellular vesicles from human multipotent stromal cells protect against hearing loss after noise trauma in vivo

Warnecke

Harre

Staecker

et al. 2020

Clinical & Translational Med

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Mesenchymal Stem Cell exosome delivered Zinc Finger Protein activation of cystic fibrosis transmembrane conductance regulator

Villamizar

Waters

Scott

et al. 2021

J of Extracellular Vesicle

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Cystic fibrosis is a genetic disorder that results in a multi-organ disease with progressive respiratory decline which leads to premature death. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disrupts the capacity of the protein to function as a channel, transporting chloride ions and bicarbonate across epithelial cell membranes. Small molecule treatments targeted at potentiating or correcting CFTR have shown clinical benefits, but are only effective for a small percentage of individuals with specific CFTR mutations. To overcome this limitation, we engineered stromal-derived mesenchymal stem cells (MSC) and HEK293 cells to produce exosomes containing a novel CFTR Zinc Finger Protein fusion with transcriptional activation domains VP64, P65 and Rta to target the CFTR promoter (CFZF-VPR) and activate transcription. Treatment with CFZF-VPR results in robust activation of CFTR transcription in patient derived Human Bronchial Epithelial cells (HuBEC). We also find that CFZF-VPR can be packaged into MSC and HEK293 cell exosomes and delivered to HuBEC cells to potently activate CFTR expression. Connexin 43 appeared to be required for functional release of CFZF-VPR from exosomes. The observations presented here demonstrate that MSC derived exosomes can be used to deliver a packaged zinc finger activator to target cells and activate CFTR. The novel approach presented here offers a next-generation genetic therapy that may one day prove effective in treating patients afflicted with Cystic fibrosis. K E Y WO R D S CFTR, exosome, cystic fibrosis, MSC, Zinc Finger Protein  SIGNIFICANCE STATEMENT Exosomes are important mediators that facilitate intercellular communication and transfer of genetic material to recipient cells. Here, we take advantage of this inherent property and engineer MSCs to produce exosomes packaged with a Zinc Finger Activator targeted to the CFTR gene promoter. We find that treatment of CF patient derived HuBEC with the CFZF-VPR containing exosomes results in significant activation of CFTR. The novel approach presented here represents an effective way to deliver therapeutic proteins to patients afflicted with CF. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Extracellular Vesicles Can Deliver Anti-inflammatory and Anti-scarring Activities of Mesenchymal Stromal Cells After Spinal Cord Injury

Cited by 68 publications

References 45 publications

Treatment of rats with spinal cord injury using human bone marrow-derived stromal cells prepared by negative selection

Treatment of rats with spinal cord injury using human bone marrow-derived stromal cells prepared by negative selection

Extracellular vesicles from human multipotent stromal cells protect against hearing loss after noise trauma in vivo

Mesenchymal Stem Cell exosome delivered Zinc Finger Protein activation of cystic fibrosis transmembrane conductance regulator

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