Review of Preclinical and Clinical Studies of Bone Marrow‐Derived Cell Therapies for Intracerebral Hemorrhage

Rosado-de-Castro, Paulo Henrique; Carvalho, Felipe Gonçalves de; Freitas, Gabriel R. de; Mendez-Otero, Rosália; Pimentel‐Coelho, Pedro M.

doi:10.1155/2016/4617983

Cited by 17 publications

(20 citation statements)

References 109 publications

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“…Importantly, these effects were achieved without changing the mesenchymal stromal cell identity of the cells or impairing their neurotrophic actions. Our results support the utilization of rBM-MSCs for the investigation of preconditioning strategies aimed at improving the efficacy of MSCs-based therapies, especially in preclinical studies in rats, which are still widely used in the field of neural regeneration [3, 28, 30, 83, 92, 93].…”

Section: Discussionsupporting

confidence: 75%

“…Mesenchymal stromal cells (MSCs), multipotent cells that can be isolated from a wide range of fetal, perinatal, and adult tissues, have emerged as a promising cell type for regenerative medicine [1, 2]. Although MSCs do not differentiate into neurons and glial cells in vivo, they have potent immunomodulatory properties and contribute to neural regeneration in a paracrine manner, which makes them an attractive option for the development of novel therapies for several neurological disorders [3–7].…”

Section: Introductionmentioning

confidence: 99%

“…To our knowledge, however, only a few studies have examined the effects of LPS and Poly(I:C) on rat bone marrow-derived MSCs (rBM-MSCs) [24–27], although rBM-MSCs are still widely used in preclinical studies. In a recent review article, for example, we identified 18 articles that have transplanted bone marrow-derived MSCs (BM-MSCs) in animal models of intracerebral hemorrhage and subarachnoid hemorrhage, 14 of which used rBM-MSCs [3]. Similarly, rBM-MSCs have been widely used in studies that have investigated the preclinical efficacy of BM-MSCs for the treatment of central and peripheral nerve disorders [4, 28].…”

Section: Introductionmentioning

confidence: 99%

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Preconditioning of Rat Bone Marrow-Derived Mesenchymal Stromal Cells with Toll-Like Receptor Agonists

Evaristo-Mendonça

Sardella-Silva

Kasai-Brunswick

et al. 2019

Stem Cells International

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Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are dynamic cells that can sense the environment, adapting their regulatory functions to different conditions. Accordingly, the therapeutic potential of BM-MSCs can be modulated by preconditioning strategies aimed at modifying their paracrine action. Although rat BM-MSCs (rBM-MSCs) have been widely tested in preclinical research, most preconditioning studies have employed human and mouse BM-MSCs. Herein, we investigated whether rBM-MSCs modify their phenotype and paracrine functions in response to Toll-like receptor (TLR) agonists. The data showed that rBM-MSCs expressed TLR3, TLR4, and MDA5 mRNA and were able to internalize polyinosinic-polycytidylic acid (Poly(I:C)), a TLR3/MDA5 agonist. rBM-MSCs were then stimulated with Poly(I:C) or with lipopolysaccharide (LPS, a TLR4 agonist) for 1 h and were grown under normal culture conditions. LPS or Poly(I:C) stimulation did not affect the viability or the morphology of rBM-MSCs and did not modify the expression pattern of key cell surface markers. Poly(I:C) did not induce statistically significant changes in the release of several inflammatory mediators and VEGF by rBM-MSCs, although it tended to increase IL-6 and MCP-1 secretion, whereas LPS increased the release of IL-6, MCP-1, and VEGF, three factors that were constitutively secreted by unstimulated cells. The neurotrophic activity of the conditioned medium from unstimulated and LPS-preconditioned rBM-MSCs was investigated using dorsal root ganglion explants, showing that soluble factors produced by unstimulated and LPS-preconditioned rBM-MSCs can stimulate neurite outgrowth similarly, in a VEGF-dependent manner. LPS-preconditioned cells, however, were slightly more efficient in increasing the number of regrowing axons in a model of sciatic nerve transection in rats. In conclusion, LPS preconditioning boosted the production of constitutively secreted factors by rBM-MSCs, without changing their mesenchymal identity, an effect that requires further investigation in exploratory preclinical studies.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Preconditioning of Rat Bone Marrow-Derived Mesenchymal Stromal Cells with Toll-Like Receptor Agonists

Evaristo-Mendonça

Sardella-Silva

Kasai-Brunswick

et al. 2019

Stem Cells International

Self Cite

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“…BM mononuclear cells (BMMC) are increasingly used as a cell therapy for a variety of brain injuries including stroke, both in preclinical and clinical settings (Rosado-de-Castro et al, 2016). While the identity of the immune cells within the heterogeneous BMMC pool responsible for the protective effects has not been established, one study showed that BMMC depleted of myeloid cells lost their protective potential after transient MCAo in rats while depletion of the lymphocyte and erythrocyte lineage had no effect (Yang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Endogenous protection from ischemic brain injury by preconditioned monocytes

García-Bonilla

Brea

Benakis

et al. 2018

Preprint

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Exposure to low dose lipopolysaccharide prior to cerebral ischemia is neuroprotective in stroke models, a phenomenon termed preconditioning. While it is well established that lipopolysaccharidepreconditioning induces central and peripheral immune responses, the cellular mechanisms modulating ischemic injury remain unclear. Here, we investigated the role of immune cells in the brain protection afforded by preconditioning and we tested whether monocytes may be reprogrammed by ex vivo lipopolysaccharide exposure thus modulating the inflammatory injury after cerebral ischemia in male mice. We found that systemic injection of low-dose lipopolysaccharide induces a distinct subclass of CD115 + Ly6C hi monocytes that protect the brain after transient middle cerebral artery occlusion in mice.Remarkably, adoptive transfer of monocytes isolated from preconditioned mice into naïve mice 7 hours after transient middle cerebral artery occlusion reduced brain injury. Gene expression and functional studies showed that IL-10, iNOS and CCR2 in monocytes are essential for the neuroprotection. This protective activity was elicited even if mouse or human monocytes were exposed ex vivo to lipopolysaccharide and then injected into male mice after stroke. Cell tracking studies showed that protective monocytes are mobilized from the spleen and reach brain and meninges, wherein they suppressed post-ischemic inflammation and neutrophils influx into the brain parenchyma. Our findings unveil a previously unrecognized subpopulation of splenic monocytes capable to protect the brain with an extended therapeutic window, and provide the rationale for cell therapies based on the delivery of autologous or allogeneic protective monocytes into patients with ischemic stroke. Significance StatementInflammation is a key component of the pathophysiology of the brain in stroke, a leading cause of death and disability with limited therapeutic options. Here, we investigate endogenous mechanisms of protection against cerebral ischemia. Using LPS preconditioning as an approach to induce ischemic tolerance in mice, we found the generation of neuroprotective monocytes within the spleen from where they traffic to the brain and meninges suppressing post-ischemic inflammation. Importantly, systemic LPS preconditioning can be mimicked by adoptive transfer of in vitro-preconditioned mouse or human monocytes at translational relevant time points after stroke. This model of neuroprotection may facilitate clinical efforts to increase the efficacy of bone marrow mononuclear cell treatments in acute neurological diseases such as cerebral ischemia.Garcia-Bonilla, page 3

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“…Clinical trials have reported beneficial effects of autologous bone marrow-derived mononuclear cells when delivered by lumbar puncture after spinal cord injury or intracerebrally into the motor cortex in ALS patients (Box 2), 73, 74 and clinical trials on bone marrow-derived mononuclear cells have also been initiated on patients with stroke or cerebral palsy. 75–77…”

Section: Clinical Trials Using Immune Cell-based Therapy — Successes mentioning

confidence: 99%

Promises and limitations of immune cell-based therapies in neurological disorders

Leak

Thomson

et al. 2018

Nat Rev Neurol

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The healthy immune system has natural checkpoints that temper pernicious inflammation. Cells mediating these checkpoints include regulatory T cells, regulatory B cells, regulatory dendritic cells, microglia, macrophages and monocytes. Here, we highlight discoveries on the beneficial functions of regulatory immune cells and their mechanisms of action and evaluate their potential use as novel cell-based therapies for brain disorders. Regulatory immune cell therapies have the potential not only to mitigate the exacerbation of brain injury by inflammation but also to promote an active post-injury brain repair programme. By harnessing the reparative properties of these cells, we can reduce over-reliance on medications that mask clinical symptoms but fail to impede or reverse the progression of brain disorders. Although these discoveries encourage further testing and genetic engineering of regulatory immune cells for the clinical management of neurological disorders, a number of challenges must be surmounted to improve their safety and efficacy in humans.

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Review of Preclinical and Clinical Studies of Bone Marrow‐Derived Cell Therapies for Intracerebral Hemorrhage

Cited by 17 publications

References 109 publications

Preconditioning of Rat Bone Marrow-Derived Mesenchymal Stromal Cells with Toll-Like Receptor Agonists

Preconditioning of Rat Bone Marrow-Derived Mesenchymal Stromal Cells with Toll-Like Receptor Agonists

Endogenous protection from ischemic brain injury by preconditioned monocytes

Promises and limitations of immune cell-based therapies in neurological disorders

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