Collagen scaffold combined with human umbilical cord-mesenchymal stem cells transplantation for acute complete spinal cord injury

Regeneration of damaged neurons and recovery of sensation and motor function after complete spinal cord injury (SCI) are challenging. We previously developed a collagen scaffold, NeuroRegen, to promote axonal growth along collagen fibers and inhibit glial scar formation after SCI. When functionalized with multiple biomolecules, this scaffold promoted neurological regeneration and functional recovery in animals with SCI. In this study, eight patients with chronic complete SCI were enrolled to examine the safety and efficacy of implanting NeuroRegen scaffold with human umbilical cord mesenchymal stem cells (hUCB-MSCs). Using intraoperative neurophysiological monitoring, we identified and surgically resected scar tissues to eliminate the inhibitory effect of glial scarring on nerve regeneration. We then implanted NeuroRegen scaffold loaded with hUCB-MSCs into the resection sites. No adverse events (infection, fever, headache, allergic reaction, shock, perioperative complications, aggravation of neurological status, or cancer) were observed during 1 year of follow-up. Primary efficacy outcomes, including expansion of sensation level and motor-evoked potential (MEP)-responsive area, increased finger activity, enhanced trunk stability, defecation sensation, and autonomic neural function recovery, were observed in some patients. Our findings suggest that combined application of NeuroRegen scaffold and hUCB-MSCs is safe and feasible for clinical therapy in patients with chronic SCI. Our study suggests that construction of a regenerative microenvironment using a scaffold-based strategy may be a possible future approach to SCI repair.

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Functional recovery in acute traumatic spinal cord injury after transplantation of human umbilical cord mesenchymal stem cells

Critical Care Medicine ◽

10.1097/ccm.0b013e3181f17c0e ◽

2010 ◽

Vol 38 (11) ◽

pp. 2181-2189 ◽

Cited By ~ 59

Author(s):

Sheng-Li Hu ◽

Hai-Shui Luo ◽

Jiang-Tao Li ◽

Yong-Zhi Xia ◽

Lan Li ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Functional Recovery ◽

Human Umbilical Cord ◽

Traumatic Spinal Cord Injury ◽

Cord Injury

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Human umbilical cord mesenchymal stem cells to treat spinal cord injury in the early chronic phase: study protocol for a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial

Neural Regeneration Research ◽

10.4103/1673-5374.274347 ◽

2020 ◽

Vol 15 (8) ◽

pp. 1532 ◽

Cited By ~ 3

Author(s):

Li-Min Rong ◽

Yang Yang ◽

Mao Pang ◽

Yu-Yong Chen ◽

Liang-Ming Zhang ◽

...

Keyword(s):

Clinical Trial ◽

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Chronic Phase ◽

Human Umbilical Cord ◽

Phase Study ◽

Cord Injury

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Human Umbilical Cord Mesenchymal Stem Cells-Secreted TSG-6 Is Anti-Inflammatory and Promote Tissue Repair After Spinal Cord Injury

ASN NEURO ◽

10.1177/17590914211010628 ◽

2021 ◽

Vol 13 ◽

pp. 175909142110106

Author(s):

Ziling Liao ◽

Wei Wang ◽

Weiyue Deng ◽

Yuying Zhang ◽

Aishi Song ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Tissue Repair ◽

Human Umbilical Cord ◽

Therapeutic Effects ◽

Cord Injury ◽

Tissue Recovery

Spinal cord injury (SCI) causes patients paralysis and hard to recover. The therapeutic effects of current clinical drugs are accompanied by side effects. In recent years, stem cell therapy has attracted the attention of researchers. Human umbilical cord mesenchymal stem cells (hucMSCs) have been widely used in various diseases due to their excellent paracrine function. TNF-stimulated gene 6 (TSG-6), a secretion factor of stem cells, may play an important role in hucMSCs in the treatment of SCI. So we conducted an experiment to explore its effect. We first observed that the expression of TSG-6 increased in SCI rats after injected with hucMSCs. Then, we used siRNA to knowdown the expression of TSG-6. We treated SCI rats with TSG-6-knockdown hucMSCs. Without TSG-6 expression, hucMSCs treatment made the tissue recovery worse and the number of Nissl bodies less. Meanwhile, neutrophils infiltrated more in the damaged parts. Our research also proved that TSG-6 may help demyelination recovering and alleviate astrocytes gathering in the injury sites. Our study revealed that hucMSCs secreted TSG-6 may decrease the degeneration of myelin sheath, reduce inflammation, decrease neuron loss and promote tissue repair. These results provided a new therapeutic factor for the treatment of SCI.

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Extracellular vesicles derived from CD73 modified human umbilical cord mesenchymal stem cells ameliorate inflammation after spinal cord injury

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01022-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Xiao Zhai ◽

Kai Chen ◽

Huan Yang ◽

Bo Li ◽

Tianjunke Zhou ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Extracellular Vesicles ◽

Inflammatory Cytokines ◽

Human Umbilical Cord ◽

M1 Polarization ◽

Cord Injury

Abstract Background Spinal cord injury (SCI) is an inflammatory condition, and excessive adenosine triphosphate (ATP) is released into the extracellular space, which can be catabolized into adenosine by CD73. Extracellular vesicles have been designed as nano drug carriers in many diseases. However, their impacts on delivery of CD73 after SCI are not yet known. We aimed to construct CD73 modified extracellular vesicles and explore the anti-inflammatory effects after SCI. Methods CD73 engineered extracellular vesicles (CD73+ hucMSC-EVs) were firstly established, which were derived from human umbilical cord mesenchymal stem cells (hucMSCs) transduced by lentiviral vectors to upregulate the expression of CD73. Effects of CD73+ hucMSC-EVs on hydrolyzing ATP into adenosine were detected. The polarization of M2/M1 was verified by immunofluorescence. Furthermore, A2aR and A2bR inhibitors and A2bR knockdown cells were used to investigate the activated adenosine receptor. Biomarkers of microglia and levels of cAMP/PKA were also detected. Repetitively in vivo study, morphology staining, flow cytometry, cytokine analysis, and ELISA assay, were also applied for verifications. Results CD73+ hucMSC-EVs reduced concentration of ATP and promoted the level of adenosine. In vitro experiments, CD73+ hucMSC-EVs increased macrophages/microglia M2:M1 polarization, activated adenosine 2b receptor (A2bR), and then promoted cAMP/PKA signaling pathway. In mice using model of thoracic spinal cord contusion injury, CD73+ hucMSC-EVs improved the functional recovery after SCI through decreasing the content of ATP in cerebrospinal fluid and improving the polarization from M1 to M2 phenotype. Thus, the cascaded pro-inflammatory cytokines were downregulated, such as TNF-α, IL-1β, and IL-6, while the anti-inflammatory cytokines were upregulated, such as IL-10 and IL-4. Conclusions CD73+ hucMSC-EVs ameliorated inflammation after spinal cord injury by reducing extracellular ATP, promoting A2bR/cAMP/PKA pathway and M2/M1 polarization. CD73+ hucMSC-EVs might be promising nano drugs for clinical application in SCI therapy. Graphical Abstract

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