Intravenous multipotent adult progenitor cell treatment decreases inflammation leading to functional recovery following spinal cord injury

DePaul, Marc A.; Palmer, Marc; Lang, Bradley T.; Cutrone, Rochelle; Tran, Amanda; Madalena, Kathryn M.; Bogaerts, Annelies; Hamilton, Jason A.; Deans, Robert; Mays, Robert W.; Busch, Sarah A.; Silver, Jerry

doi:10.1038/srep16795

Cited by 57 publications

(58 citation statements)

References 74 publications

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“…There was up-regulation of IDO, M2 polarization, endogenous neurogenesis, and gap junction formation, accompanied by down-regulation of proinflammatory cytokines, T-cells, and M1 macrophages (22,23,32,39,50), all in site-specific actions realized through tailored PLGA scaffolding of hMSCs and in a manner essentially unachievable for repairing open wounds by hMSC-conditioned medium or nonscaffolded cells. Hence, the notion of implanting stem cells pre-or postdifferentiated to a neural lineage may be working at cross-purposes to the developmental imperatives of the multipotent cells in certain cases, particularly for systemic repair of complex organs such as the spinal cord and brain (25,32,33). Our results suggest that scaffolded hMSCs may be adaptable for implantation directly into the contused spinal cord of patients in the subacute phase after injury when autoimmune and inflammatory insults peak (4,33,41,48).…”

Section: Discussionmentioning

confidence: 79%

“…Hence, the notion of implanting stem cells pre-or postdifferentiated to a neural lineage may be working at cross-purposes to the developmental imperatives of the multipotent cells in certain cases, particularly for systemic repair of complex organs such as the spinal cord and brain (25,32,33). Our results suggest that scaffolded hMSCs may be adaptable for implantation directly into the contused spinal cord of patients in the subacute phase after injury when autoimmune and inflammatory insults peak (4,33,41,48).…”

Section: Discussionmentioning

confidence: 79%

“…The inflammatory cascade paradoxically contributes to both postinjury neural damage and repair (23,31), so that subtly tuned antiinflammation capability has become a focus for treating CNS trauma (32)(33)(34). Based on the antiinflammatory and antiautoimmunity effects of scaffolded hMSCs in vitro (Fig.…”

Section: Motosensory Recovery After Sci Resulting From Scaffolded Hmscmentioning

confidence: 99%

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Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Ropper

Thakor

Han

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mesenchymal stromal stem cells (MSCs) isolated from adult tissues offer tangible potential for regenerative medicine, given their feasibility for autologous transplantation. MSC research shows encouraging results in experimental stroke, amyotrophic lateral sclerosis, and neurotrauma models. However, further translational progress has been hampered by poor MSC graft survival, jeopardizing cellular and molecular bases for neural repair in vivo. We have devised an adult human bone marrow MSC (hMSC) delivery formula by investigating molecular events involving hMSCs incorporated in a uniquely designed poly(lactic-co-glycolic) acid scaffold, a clinically safe polymer, following inflammatory exposures in a dorsal root ganglion organotypic coculture system. Also, in rat T9-T10 hemisection spinal cord injury (SCI), we demonstrated that the tailored scaffolding maintained hMSC stemness, engraftment, and led to robust motosensory improvement, neuropathic pain and tissue damage mitigation, and myelin preservation. The scaffolded nontransdifferentiated hMSCs exerted multimodal effects of neurotrophism, angiogenesis, neurogenesis, antiautoimmunity, and antiinflammation. Hindlimb locomotion was restored by reestablished integrity of submidbrain circuits of serotonergic reticulospinal innervation at lumbar levels, the propriospinal projection network, neuromuscular junction, and central pattern generator, providing a platform for investigating molecular events underlying the repair impact of nondifferentiated hMSCs. Our approach enabled investigation of recovery neurobiology components for injured adult mammalian spinal cord that are different from those involved in normal neural function. The uncovered neural circuits and their molecular and cellular targets offer a biological underpinning for development of clinical rehabilitation therapies to treat disabilities and complications of SCI.spinal cord injury | recovery neurobiology | mesenchymal stromal stem cell | PLGA | locomotion R epair of neurotrauma, stroke, and neurodegenerative diseases remains an unmet medical demand because of their pathophysiological complexity and the limited spontaneous healing capacity of adult mammalian CNS. Human mesenchymal stromal stem cells (hMSCs) offer autologous transplantation feasibility (1-4) and have been studied both experimentally and clinically for traumatic brain injury (TBI) and spinal cord injury (SCI) (5-8). Although MSCs possess homeostatic and proneurogenic activities (7, 9), studies relying on neural transdifferentiation (i.e., putative differentiations of MSCs into neural cells without reentering the pluripotency phase) did not show long-term functional improvement in SCI models. The poor outcomes were attributed mainly to suboptimal survival of MSCs, leaving key therapeutic mechanisms undetermined (10). We previously established a 3D cell delivery technology by seeding neural stem cells (NSCs) in biodegradable polymer scaffolds that significantly improved donor efficacy and enabled investigation of NSC repair mechanisms in t...

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 79%

Section: Motosensory Recovery After Sci Resulting From Scaffolded Hmscmentioning

confidence: 99%

See 1 more Smart Citation

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Ropper

Thakor

Han

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The high disability and mortality rates of SCI often have a huge physiological and psychological effect on individuals, their families and society (2). However, there is no effective treatment due to the complicated pathophysiological mechanism of SCI, although numerous clinical and animal studies have been conducted (3,4).…”

Section: Introductionmentioning

confidence: 99%

Anti‑inflammatory effect of delphinidin on intramedullary spinal pressure in a spinal cord injury rat model

Wang

Zhu

et al. 2017

Exp Ther Med

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Abstract. Delphinidin, a flavonoid polyphenolic compound, is widely found in nature and is used as a food supplement due to its pharmacological activity. The aims of the present study were to examine the anti-inflammatory effect of delphinidin in alleviating spinal cord injury (SCI)-induced inflammation in a rat model and to determine the underlying mechanisms in SCI. The Basso, Beattie, Bresnahan (BBB) scores of rats were assessed to evaluate the effect of delphinidin on the recovery of motor function. ELISA kits were also used to analyze the activities of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and caspase-3. In addition, the protein expression levels of nuclear factor (NF)-κB, activator protein 1 (AP-1) and p38-MAPK protein expression were measured using western blot analysis. Treatment with delphinidin significantly increased the BBB scores, as well as inhibited the intramedullary spinal pressure in SCI rats. Delphinidin treatment also significantly suppressed the levels of inflammatory factors and NF-κB protein expression in SCI rats. Finally, treatment with delphinidin significantly inhibited NF-κB stimulation, COX-2 activity, PGE2 production, and AP-1 and p38-MAPK protein expression in SCI rats. These results suggest that the anti-inflammatory effect of delphinidin alleviated inflammation in the SCI rat model via alleviation of the intramedullary spinal pressure through the NF-κB and p38-MAPK signaling pathways.

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“…Multiple preclinical studies investigating MultiStem's administration have provided insights into the cells' mechanisms of action, including neurotrophic and/or neuroprotective improvements in animal models with neonatal hypoxicischemic encephalopathy or focal ischemia [20][21][22][23][24][25] as well as significant reduction in inflammatory cascades and immune modulation in rodents with traumatic brain injury and spinal cord injury [23,24,[26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Lab-to-clinic application of stem cell therapy for stroke

2016

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Stem cell therapy or "cell therapy" has been demonstrated to be a potent treatment intervention in animal models of acute ischemic stroke, and recently has been introduced as an experimental therapy in early phase clinical trials. Among the many stem cells, the bone marrow adherent cell type known as mesenchymal stem cells have emerged in laboratory studies as a safe and effective therapy for ischemic stroke and other brain diseases. In particular, a unique population of adherent bone marrow-derived cells, called MultiStem cells, display immunomodulatory effects and are a promising allogeneic cell therapy in acute ischemic stroke. Here, we describe the preclinical evidence supporting the use of MultiStem in the acute setting of ischemic stroke and the translation into an early phase clinical trial in ischemic stroke.

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Intravenous multipotent adult progenitor cell treatment decreases inflammation leading to functional recovery following spinal cord injury

Cited by 57 publications

References 74 publications

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Anti‑inflammatory effect of delphinidin on intramedullary spinal pressure in a spinal cord injury rat model

Lab-to-clinic application of stem cell therapy for stroke

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