Therapeutic time window and dose response of autologous bone marrow mononuclear cells for ischemic stroke

Yang, Bing; Strong, Roger; Sharma, Sushil; Brenneman, Miranda M.; Kasam, Mallikarjunarao; Xi, Xiaopei; Grotta, James C.; Aronowski, Jaroslaw; Savitz, Sean I

doi:10.1002/jnr.22614

Cited by 91 publications

(84 citation statements)

References 14 publications

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“…This methodology is supported by a preclinical study in which rats with common carotid artery/middle cerebral artery occlusion performed better on neurologic tests with IV mononuclear cells infused up to 72 hours, compared with 1 week from stroke onset. 15 However, similar to prior animal experiments, this study also found cells sequestered in the spleen, lung, liver, and kidney.…”

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confidence: 88%

Stem cell therapy in ischemic stroke

et al. 2012

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Objective: Cell-based therapies are being investigated as an adjunct to IV thrombolysis or mechanical thrombectomy in ischemic stroke. This review summarizes the potential applications as well as challenges of intravascular cell delivery in ischemic stroke. Method:We conducted a search of Medline as well as the clinicaltrials.gov Web site for all ongoing human clinical studies using stem cells in ischemic stroke patients. Result:The pros and cons of the various donor cell types and routes of cell delivery, including intravascular delivery, in ischemic stroke are discussed. In addition, the potential challenges in translation from bench to bedside, the optimal techniques for intravascular cell delivery, and an updated comprehensive list of ongoing clinical trials in ischemic stroke are highlighted. Conclusions:Stem cells have shown a promising role in ischemic stroke, in preclinical studies as well as initial pilot studies. Further studies are needed to assess intravascular cell therapy as a potential adjunct to thrombolysis or mechanical thrombectomy in ischemic stroke. Neurology Cell therapy is emerging as a promising new modality for enhancing neurologic recovery in ischemic stroke.1 Numerous basic science studies have demonstrated positive results in animal models of ischemic stroke following implantation of progenitor cells derived from various sources, including adipose, human fetal/embryonic tissue, bone marrow, peripheral, and umbilical cord blood (figure).2 These animal studies have utilized various methods of cell delivery or implantation (table 1), including direct intracerebral (IC) injection, intracisternal/cerebroventricular (ICV), or intravascular routes of delivery such as IV or intra-arterial (IA) infusion.Methods of cellular delivery and implantation. Intracerebral. Direct injection is invasive, and despite being a precise method of cellular delivery and implantation, it results in a poor distribution of cells in the target lesion.3 Initial pilot human studies investigating stereotactic IC cell implantation in patients with chronic stroke also reported adverse events, including seizures, syncope, asymptomatic subdural hematoma, transient motor worsening, and enhancing lesions on MRI. 4,5Intracisternal/cerebroventricular. The ICV route of cell delivery is less invasive than direct IC implantation but is also associated with variable cell migration to the ischemic site.6,7 In a pilot human study investigating ICV delivery in 10 chronic stroke patients (7 ischemic and 3 hemorrhagic), some patients developed fever and meningeal signs 48 hours after cellular delivery via ICV route. IV.Infusion is the least invasive method, allowing wide distribution of cells with exposure to chemotactic signals that potentially guide them toward the target ischemic lesion. This method, however, results in cells being trapped by peripheral organs, including the lungs, liver, and spleen, thereby limiting potential engraftment in the ischemic lesion in the brain.2 Since patients with ischemic stroke commonly ha...

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confidence: 88%

Stem cell therapy in ischemic stroke

et al. 2012

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“…These findings led to determining the therapeutic window of MNC-mediated recovery following AIS. 61 A detailed description of cell-based therapy in AIS has also been provided. 62 Furthermore, it was discovered for the first time that bone marrow-derived MNCs protect cortical neurons by modulating microglia in a cell culture model of AIS; additionally, the basic molecular mechanism of neuroprotection afforded by MNCs was elucidated.…”

Section: Mts As Early and Sensitive Biomarkers Of Nps Toxicitymentioning

confidence: 99%

Clinical significance of metallothioneins in cell therapy and nanomedicine

Sharma¹,

Rais²,

Sandhu³

et al. 2013

IJN

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Mammalian metallothioneins (MTs) are low molecular weight (6-7 kDa) cysteinerich proteins that are specifically induced by metal nanoparticles (NPs). MT induction in cell therapy may provide better protection by serving as antioxidant, anti-inflammatory, antiapoptotic agents, and by augmenting zinc-mediated transcriptional regulation of genes involved in cell proliferation and differentiation. Liposome-encapsulated MT-1 promoter has been used extensively to induce growth hormone or other genes in culture and gene-manipulated animals. MTs are induced as a defensive mechanism in chronic inflammatory conditions including neurodegenerative diseases, cardiovascular diseases, cancer, and infections, hence can serve as early and sensitive biomarkers of environmental safety and effectiveness of newly developed NPs for clinical applications. Microarray analysis has indicated that MTs are significantly induced in drug resistant cancers and during radiation treatment. Nutritional stress and environmental toxins (eg, kainic acid and domoic acid) induce MTs and aggregation of multilamellar electron-dense membrane stacks (Charnoly body) due to mitochondrial degeneration. MTs enhance mitochondrial bioenergetics of reduced nicotinamide adenine dinucleotide-ubiquinone oxidoreductase (complex-1), a rate-limiting enzyme complex involved in the oxidative phosphorylation. Monoamine oxidase-B inhibitors (eg, selegiline) inhibit α-synuclein nitration, implicated in Lewy body formation, and inhibit 1-methyl 4-phenylpyridinium and 3-morpholinosydnonimineinduced apoptosis in cultured human dopaminergic neurons and mesencephalic fetal stem cells. MTs as free radical scavengers inhibit Charnoly body formation and neurodegenerative α-synucleinopathies, hence Charnoly body formation and α-synuclein index may be used as early and sensitive biomarkers to assess NP effectiveness and toxicity to discover better drug delivery and surgical interventions. Furthermore, pharmacological interventions augmenting MTs may facilitate the theranostic potential of NP-labeled cells and other therapeutic agents. These unique characteristics of MTs might be helpful in the synthesis, characterization, and functionalization of emerging NPs for theranostic applications. This report highlights the clinical significance of MTs and their versatility as early, sensitive biomarkers in cell-based therapy and nanomedicine.

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“…Some, preclinical studies have indicated that only small number of cells reaching the ischemic brain after systemic administration, many of these leads to cell arrest in organs like the lungs, liver or spleen [70]. Intra-arterial route of delivery of MSCs, but not Bone Marrow Mononuclear Cells (BM-MNCs), was associated with new ischemic attack and increased mortality in animal model.…”

Section: Discussionmentioning

confidence: 99%