Editorial Open Access
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Stem Cells. Feb 26, 2011; 3(2): 9-18
Published online Feb 26, 2011. doi: 10.4252/wjsc.v3.i2.9
Progenitor cells as remote "bioreactors": Neuroprotection via modulation of the systemic inflammatory response
Peter A Walker, Phillip A Letourneau, Shinil K Shah, Charles S Cox Jr, Department of Surgery, University of Texas Medical School at Houston, Houston, TX 77030, United States
Peter A Walker, Supinder Bedi, Shinil K Shah, Fernando Jimenez, Charles S Cox Jr, Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, TX 77030, United States
Shinil K Shah, Charles S Cox Jr, Michael E DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas A & M University, College Station, TX 77840, United States
Author contributions: Walker PA, Letourneau PA, Bedi S, Shah SK, Jimenez F and Cox CS Jr wrote this editorial together.
Supported by Grants NIH T32 GM 08 79201; M01 RR 02558; Texas Higher Education Coordinating Board; Children’s Memorial Hermann Hospital Foundation
Correspondence to: Charles S Cox Jr, MD, Department of Pediatric Surgery, University of Texas Medical School at Houston, 6431 Fannin Street, MSB 5.236, Houston, TX 77030, United States. charles.s.cox@uth.tmc.edu
Telephone: +1-713-5007307 Fax: +1-713-5007296
Received: May 19, 2010
Revised: January 5, 2011
Accepted: January 12, 2011
Published online: February 26, 2011

Abstract

Acute central nervous system (CNS) injuries such as spinal cord injury, traumatic brain injury, autoimmune encephalomyelitis, and ischemic stroke are associated with significant morbidity, mortality, and health care costs worldwide. Preliminary research has shown potential neuroprotection associated with adult tissue derived stem/progenitor cell based therapies. While initial research indicated that engraftment and transdifferentiation into neural cells could explain the observed benefit, the exact mechanism remains controversial. A second hypothesis details localized stem/progenitor cell engraftment with alteration of the loco-regional milieu; however, the limited rate of cell engraftment makes this theory less likely. There is a growing amount of preclinical data supporting the idea that, after intravenous injection, stem/progenitor cells interact with immunologic cells located in organ systems distant to the CNS, thereby altering the systemic immunologic/inflammatory response. Such distant cell “bioreactors” could modulate the observed post-injury pro-inflammatory environment and lead to neuroprotection. In this review, we discuss the current literature detailing the above mechanisms of action for adult stem/progenitor cell based therapies in the CNS.

Key Words: Traumatic brain injury, Cerebral stroke, Spinal cord injury, Stem cells, Bone marrow, Inflammation



INTRODUCTION

Acute central nervous system (CNS) injuries such as spinal cord injury (SCI), traumatic brain injury (TBI), and ischemic stroke are associated with significant worldwide morbidity and mortality. Up to 5 million people are burdened by the morbidity associated with TBI annually with approximately 40% of patients reporting unmet needs 1 year after injury[1]. In addition, an initial cerebrovascular accident is associated with a lifelong loss of 9.5 quality adjusted life years[2]. Overall, the combined economic impact of SCI, TBI, and ischemic stroke surpasses several billion dollars annually in the United States[3,4].

Early preclinical research has shown potential benefit from adult tissue progenitor cell therapy for acute and chronic CNS injury. Adult tissue stem/progenitor cells are maintained in select microenvironments or niches throughout the body. Within the niche, stem cell proliferation, depletion, and involvement in resident tissue regeneration and repair is tightly regulated[5]. Stem/progenitor cells are prime candidates for novel therapies due to their observed capacity for self renewal and ability to differentiate down multiple cell lines[6].

Preliminary in vivo and in vitro research has shown potential benefit associated with stem/progenitor cell therapy after TBI[7], ischemic stroke[8], and SCI[9]. While initial research indicated that engraftment and transdifferentiation into neural cells could explain the observed benefit[10], the exact mechanism remains controversial. A second hypothesis details localized stem/progenitor cell engraftment with alteration of the loco-regional milieu; however, the limited rate of cell engraftment makes this theory less likely. There is a growing amount of preclinical data supporting the idea that, after intravenous injection, stem/progenitor cells interact with immunologic cells located in organ systems distant to the CNS thereby altering the systemic immunologic/inflammatory response. Such distant cell “bioreactors” could modulate the observed post-injury pro-inflammatory environment and lead to neuroprotection.

ENGRAFTMENT AND TRANSDIFFERENTIATION

Early preclinical research hypothesized that transplanted bone marrow-derived mesenchymal stromal cells (MSCs) could migrate and engraft at the site of injury and adopt neuronal cell markers indicating their differentiation into neurons [neuronal nuclei (NeuN)] and astrocytes [glial fibrillary acidic protein (GFAP)][11]. Additional work completed by Hayase et al[12] showed induction of neurospheres from MSCs in vitro. The neurospheres were then implanted into rodent cerebral cortex after focal ischemic injury and remained engrafted at the injury site for up to 100 d. The engrafted progenitor cells displayed neural markers with a concordant improvement in animal behavioral recovery[12]. Using a rodent spinal cord injury model, the Ha laboratory implanted human umbilical cord blood mononuclear cells (HUCBCs) into the injury region and found engrafted HUCBCs up to 8 wk after injury. HUCBCs were found to express the neural markers GFAP and microtubule-associated protein 2 (MAP2). Functional improvement via locomotor testing was observed in the animals for up to 8 wk[13].

Such preliminary work investigating the intravenous infusion of MSCs has been promising. However, much debate remains about the frequency and clinical significance of progenitor cell “transdifferentiation” and the validity of neural marker expression with most investigators believing this to be erroneous[14-16]. Coyne et al[17] showed that MSCs labeled with BrdU transferred their label to replicating neurons and gave the erroneous impression that MSCs were expressing these proteins when double labels were used. In addition, hematopoietic stem cells (HSCs) implanted into a spinal cord injury site[18] and murine striatum[16] failed to transdifferentiate into neurons and actually showed differentiation into macrophages and microglia. Furthermore, Hunt et al[19] observed the failure of transdifferentiation with collagen deposition and axonal injury after the implantation of MSCs into demyelinated spinal cord.

Additional in vitro research has been carried out to investigate the capacity for stem/progenitor cell transdifferentiation in to neurons. Barnabe et al[20] have shown that MSCs could be chemically induced to produce the neuronal proteins NF-200, S100, β-tubulin III, NSE and MAP-2; however, the cells had an apoptotic rate greater than 50%. In vitro electrophysiological recordings did not show neuronal properties as no sodium / potassium gradients or action potentials were observed[20]. Further research has shown that bone marrow derived multipotent adult progenitor cells (MAPCs) express the neural proteins β III tubulin and NF200 at baseline. Culture of MAPCs in neural differentiation media failed to upregulate protein expression, indicating that the appearance of neural transdifferentiation based upon neural antigen expression can be misleading[21]. While preliminary work pointed towards transdifferentiation as a potential mechanism for cognitive improvement, a large body of preclinical research now indicates that this is an unlikely pathway towards functional benefit.

MODULATION OF THE LOCO-REGIONAL INFLAMMATORY RESPONSE

The observed functional benefit observed with intravenous stem/progenitor cell therapy could be secondary to localized engraftment and interaction with resident microglia leading to modulation of the loco-regional milieu. Work completed in the Cox laboratory measured the concentration of the pro-inflammatory cytokines interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, found in cortical tissue after TBI in a rodent model. A multiplex cytokine assay showed an increase in all of the measured pro-inflammatory cytokines measured (IL-1α, IL-1β, IL-6, and TNF-α) in the direct injury and penumbral areas of the injured brain as shown in Figure 1[22]. These results detail the post injury pro-inflammatory response and identify a potential target for novel therapies.

Figure 1
Figure 1 Elevated intracerebral cytokines identified in specific areas and at specific time points relative to the traumatic brain injury. The proinflammatory cytokines interleukin (IL)-1α (A), IL-1β (B), IL-6 (C), and tumor necrosis factor-α (D) were significantly elevated 6 h after CCI in the injury and penumbral regions when compared with sham animals (bP < 0.01 for all). IL-1α, IL-1β, and IL-6 remained elevated through 12, 12 and 24 h, respectively (bP < 0.01 or aP < 0.05). In the frontal area, IL-6 was significantly increased at 24 h (33- to 50-fold; P < 0.01; Dunnett's test), but not at 6 or 12 h after traumatic brain injury. Reproduced with permission[22].

Early in vitro work investigated the co-culture of human immunologic cells with MSCs and showed an increase in production of the anti-inflammatory cytokines IL-4 and IL-10 in accordance with a decrease in production of the pro inflammatory cytokine interferon γ (IFN-γ). Additionally, an increase in T regulatory cell (a known mediator if the anti-inflammatory response) differentiation was observed[23]. Walker et al[24] found an increase in the cytokine interleukin 6 (IL-6) in rodent brain tissue supernatant after the direct intrathecal implantation of MSCs using a TBI model. To explore the potential mechanisms of action, a series of in vitro MSC and neuronal stem cell (NSC) co-culture experiments was devised. Direct contact co-culture led to activation of the NSC NFκB pathway with a concordant decrease in NSC apoptosis which was not replicated in transwell (non contact) cultures, indicating the need for direct MSC/NSC contact for effect[24]. Additional work investigating the direct intracerebral implantation of MSCs using a stroke model found increased intracerebral IL-10 with a corresponding decrease in TNF-α production. The observed modulation of the loco-regional milieu led to functional improvement[25]. Pluchino et al[26] have shown that the intravenous delivery of neurosphere-derived stem/progenitor cells in a chronic CNS inflammatory model leads to the engraftment of cells in perivascular niches. Upon engraftment, the neurosphere-derived cells induce apoptosis in circulating blood born T cells thereby decreasing the amount of inflammatory neuronal injury[26]. Such preliminary work has shown a potential mechanism to explain the observed benefit; however, the majority of studies are based upon the direct intracerebral or intrathecal implantation of progenitor cells.

A potential barrier to the direct implantation of stem/progenitor cells is related to the size or the multifocality of the lesion. A significant injury cavity can occur after TBI, SCI, or ischemic stroke that could potentially require multiple stereotactic injections (needle tracts) which could exacerbate the inflammatory response to injury. More commonly, there are multiple foci of diffuse injury that would make stereotactic implantation impractical. In order to circumvent the need for multiple injections, alternate delivery methods such as intravenous injection need to be considered.

The intravenous delivery of stem/progenitor cells is attractive subject to the potential for widespread distribution and the lack of invasiveness from the procedure. Biodistribution studies completed by Fischer et al[27] have shown that the vast majority of injected progenitor cells remain sequestered in the lungs, as illustrated in Figure 2, and have described this as a significant pulmonary first pass effect[27]. These findings have been replicated by many investigators with Harting et al[28] showing only 0.001% of intravenously transplanted cells engrafted in the brain parenchyma with significant sequestration of MSCs in the lung up to 3 d after injection. Additionally, Lee et al[29] found significant pulmonary sequestration with only 0.001% of intravenously injected MSCs in any distant organ system.

Figure 2
Figure 2 Fluorescent imaging of QDOT (green) labeled mesenchymal stromal cells, neuronal stem cells, multipotent adult progenitor cells, and bone marrow mononuclear cells after intravenous injection. Less than 1% of mesenchymal stromal cells (MSCs) bypassed the lungs into the arterial circulation (as shown by high levels of green fluorescence). A two fold increase in pulmonary bypass was observed with neuronal stem cells (NSCs) and multipotent adult progenitor cells (MAPCs) with a 50 fold increase observed with bone marrow mononuclear cells (BMMCs). Reproduced with permission[48].

The observed significant pulmonary first pass effect greatly decreases the number of stem/progenitor cells that reach the systemic circulation, thereby limiting the quantity that could interact with the injury area and engraft. It is possible that only a few MSCs are needed to activate resident microglia leading to modulation of the loco regional inflammatory/immunologic response. However, emerging data indicates that the hypothesis of stem/progenitor cells acting as local “bio-reactors” seems more unlikely and requires further investigation.

MODULATION OF THE SYSTEMIC INFLAMMATORY RESPONSE

The intravenous delivery of stem/progenitor cells remains the ideal delivery vehicle due to the potential for widespread distribution and simplicity although cell delivery is limited by a significant pulmonary first pass effect. Despite the limited number of cells reaching the systemic circulation, multiple investigators have reported neuroprotection with intravenous therapy[30,31]. Such results indicate that it may not be necessary for a large number of cells to reach the injury zone to produce effect. It is also possible that the stem/progenitor cells are interacting with immunologic cells in remote organ systems and acting as distant “bioreactors” which alter the systemic inflammatory/immunologic response and lead to the observed benefit. The possible locations of remote progenitor/immunologic cell interactions include the lung, spleen, liver, lymph nodes, and kidney.

Pulmonary immunologic cells

Secondary to the significant pulmonary first pass effect, the majority of stem/progenitor cells are sequestered within the lung after intravenous injection, indicating a high probability of interaction between the transplanted cells and resident pulmonary immunologic cells[27]. Mei et al[32] found a reduction in lipopolysaccharide (LPS)-induced pulmonary inflammation after the intravenous injection of MSCs in a murine acute lung injury model. A further reduction in alveolar inflammation and permeability was observed when the MSCs were transfected with vasculoprotective gene angiopoietin 1 (ANGPT1) prior to injection. A reduction in neutrophils as well as the pro inflammatory cytokines IFN-γ, TNF-α, IL-6 and IL-1β was found with both treatment groups[32].

A recent study completed in the Mezey laboratory investigated the effect of intravenous MSC therapy on systemic inflammation due to sepsis using a murine cecal ligation and puncture (CLP) model. This seminal study characterized the cellular interactions between MSCs and lung-derived monocytes/macrophages. MSC treatment improved survival, organ function and reduced pro-inflammatory cytokines (TNF-α and IL-6) in the serum, as shown in Figure 3. The injected MSCs were found to directly interact with pulmonary macrophages resulting in an increase in serum levels of IL-10, which is produced by monocytes and macrophages[33] and associated with a reduction in the migration of neutrophils[34] and decreased oxidative damage[35]. The role of IL-10 production in the observed improvement in mortality and end organ function was confirmed via a series of experiments using IL-10 knockout mice and IL-10 receptor antibodies as shown in Figure 4. Furthermore, a series of in vitro and in vivo experiments was completed showing that MSC derived prostaglandin E2 production stimulated resident macrophages to produce IL-10 via activation through EP2 and EP4 receptors[36].

Figure 3
Figure 3 Effect of intravenous injection of BMSCs on the course of sepsis after cecal ligation and puncture. A: Survival curves of mice after cecal ligation and puncture (CLP) and a variety of treatments using BMSCs from C57/BL6, FVB/NJ and BALB/c mice, as well as C57/BL6-derived fibroblasts; B: BMSC treatment effects on kidney function, as reflected by serum concentration of creatinine (SCr). The number of mice in all measurements is as follows: sham, n = 5; CLP, n = 13; CLP + BMSC, n = 14. Tubular injury scores are shown at right; C: Intense PAS staining of hepatocytes is shown after sham operation and BMSC treatment. No staining can be seen in CLP. After treatment (CLP + BMSC), the red staining by PAS in hepatocytes indicates partial glycogen storage capacity. Scale bar, 20 μm; D: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations in the liver after sham and BMSC, CLP or CLP and BMSC treatment; E: Serum amylase concentrations after sham and BMSC, CLP or CLP and BMSC treatment; F: DAB staining of caspase-3 cells in untreated spleen sections and BMSC-treated spleen sections. A quantitative comparison between the numbers of apoptotic splenic cells in treated versus untreated mice (right) shows a significant decrease with BMSC treatment. Scale bar, 100 μm; G: Serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 concentrations after sham and BMSC, CLP or CLP and BMSC treatment; H: Serum IL-10 concentrations at 3, 6 and 12 h after CLP. n = 8-11 at each time point. Error bars represent means ± SE; aP < 0.05; bP < 0.01. Reproduced with permission[36].
Figure 4
Figure 4 Fate of injected BMSCs and effect of BMSC treatment on survival of normal and immune cell-depleted mice. A-C Immunohistochemical staining showing that BMSCs pre-labeled with Q-dot (red punctate staining; (A) travel to the lung (B) and take up residence in close proximity to macrophages (C); The latter cells were immunostained with an antibody to Iba1 (ionized calcium-binding adaptor molecule-1, a specific marker of the macrophage lineage47) and visualized with Alexa-Fluor-488 conjugated to a secondary antibody (green). Scale bar, 10 μm; (D-F) Summary of the effectiveness of BMSC treatment of mice genetically lacking or depleted of certain subsets of immune cells or soluble mediators. Survival curves show survival percentage of macrophage-depleted mice with or without BMSC treatment (D), survival percentage of BMSC-treated CLP mice and untreated mice after neutralizing IL-10 or blocking the IL-10 receptor (e) and survival percentage of after treatment with BMSCs derived from Il10-/- septic mice (F). aP < 0.05. Reproduced with permission[36].

These preliminary studies have shown the potential importance of interactions between transplanted stem/progenitor cells and pulmonary macrophages. The observed interaction appears to modulate both the local and systemic inflammatory response increasing anti- inflammatory cytokine production which could lead to enhanced neuroprotection.

Interaction with splenocytes

Recent work completed in the Pennypacker laboratory has shown the release of immunologic T cells from the spleen into the systemic circulation with a concordant reduction in splenic mass after ischemic stroke in a rodent model. Adrenergic output appeared to mitigate this effect as treatment with the pan adrenergic blocker, carvediol, reversed the observed loss in splenic mass and reduced stroke cavity volume[37]. Vendrame et al[38] showed that the observed reduction in splenic mass associated with ischemic stroke was likely due to the release of cytotoxic CD8+ T cells which could contribute to the secondary injury seen after stroke. Injection of HUCBCs 24 h after ischemic stroke restored splenic mass, secondary to the retention of the splenocyte derived cytotoxic T cells. Results also showed a reduction in injury cavity volume as well as an increase in IL-10 and decreases in the pro inflammatory cytokines TNF-α and INF-γ[38].

Similar work carried out by Schwarting et al[39] using a rodent ischemic stroke model has shown increased levels of the pro-inflammatory cytokines TNF-α and IL-1β in the serum as well as chemokine receptor 2 and CX3CR1 within splenocytes. After intravenous injection, HSCs were found primarily in the spleen with levels of TNF-α, IL-1β, CX3CR1, and chemokine receptor 2 towards sham levels. A reduction in microglial activation and macrophage infiltration was also observed in the peri-injury parenchyma with a concordant decrease in injury cavity volume and neuronal cell apoptosis[39].

Lee et al[40] have investigated the role of NSC therapy for the treatment of intracerebral hemorrhage in a rodent model. The intravenous injection of human NSCs 2 h after injury was associated with improved functional outcomes and decreased cerebral edema as well as decreased intracerebral inflammatory infiltration and neuronal apoptosis. In addition, a reduction in the pro inflammatory cytokines TNF-α and IL-6 was measured in the brain and spleen. Histology completed to track the NSCs showed very few to be engrafted in the cortical tissue; however, a higher number of NSCs were found in the marginal zone of the spleen. Further experiments completed with a non-specific cell line (fibroblasts) or with rats after splenectomy failed to show functional benefit or decreased edema, thereby confirming the need for the splenocyte/progenitor cell interaction to obtain the observed immunomodulation[40].

These data represent a growing field of research into the role of the spleen in post injury inflammation and the ways that progenitor cells may modulate that response. In stroke models, progenitor cell therapy has been shown to preserve splenic mass and modulate the inflammatory response. More studies are required to further investigate the mechanism of immunomodulation in order to optimize the timing and dosage for cell delivery.

Other distant organ systems

The Uccelli laboratory recently completed a series of in vivo and in vitro experiments to investigate the potential role of MSCs in a murine experimental autoimmune encephalomyelitis (EAE) model. Co-culture of MSCs and T cells inhibited T cell proliferation with a concordant decrease in TNF-α and IFNγ production. The intravenous injection of MSCs in the murine encephalomyelitis model showed MSC engraftment in the lymphoid tissue and a decrease in the autoimmune response secondary to T cell unresponsiveness[41]. Additional work carried out by Kassis et al[42] using a similar model showed engraftment in lymphoid tissue associated with a decrease in both mortality and CNS inflammation as well as protection of the resident axons.

Research completed by Refei et al[43] using a murine EAE model showed a decrease in spinal cord CD4+ T cell infiltration associated with the amelioration of symptoms after the intraperitoneal injection of MSCs. The observed benefit is secondary to the inhibition of CD4+ T cell activation via suppression of STAT3 phosphorylation by MSC-derived CCL2[43].

There is limited data on the interaction of implanted adult stem/progenitor cells with other organ systems in the setting of neurological injury. Distribution studies have demonstrated stem/progenitor cells to engraft in the liver and kidney as well as the lung and spleen[44-47]. At the time of this review, there is no published data on the liver and/or kidney acting as potential bioreactors to modulate the systemic inflammatory or immune response.

CONCLUSION

Preliminary research has shown the potential benefit of adult tissue stem/progenitor cell therapy for a wide array of acute and chronic CNS injuries. While initial work indicated that the transdifferentiation of stem/progenitor cells into new neurons could account for the observed neuroprotection, the frequency of CNS engraftment and clinical significance of transdifferentiation remains controversial. A growing amount of evidence supports the idea that injected stem/progenitor cells interact with distant organ systems and immunologic cells leading to modulation of the systemic inflammatory response. Multiple investigators have shown a decrease in the pro-inflammatory response to injury which could account for the observed neuroprotection. Such promising work should stimulate the design of additional pre-clinical experiments to further outline the therapeutic mechanism prior to implementation of clinical trials.

Footnotes

Peer reviewers: Angela Gritti, PhD, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Via Olgettina, 58 -20132 Milano, Italy; Ludwig Aigner, PhD, Professor, Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, A-5020 Salzburg, Austria

S- Editor Wang JL L- Editor Hughes D E- Editor Ma WH

References
1.  Thompson HJ. A critical analysis of measures of caregiver and family functioning following traumatic brain injury. J Neurosci Nurs. 2009;41:148-158.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Lee HY, Hwang JS, Jeng JS, Wang JD. Quality-adjusted life expectancy (QALE) and loss of QALE for patients with ischemic stroke and intracerebral hemorrhage: a 13-year follow-up. Stroke. 2010;41:739-744.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Faul M, Wald MM, Rutland-Brown W, Sullivent EE, Sattin RW. Using a cost-benefit analysis to estimate outcomes of a clinical treatment guideline: testing theBrain Trauma Foundation guidelines for the treatment of severe traumatic brain injury. J Trauma. 2007;63:1271-1278.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke. 1996;27:1459-1466.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Scadden DT. The stem-cell niche as an entity of action. Nature. 2006;441:1075-1079.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Weiner LP. Definitions and criteria for stem cells. Methods Mol Biol. 2008;438:3-8.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Qu C, Mahmood A, Lu D, Goussev A, Xiong Y, Chopp M. Treatment of traumatic brain injury in mice with marrow stromal cells. Brain Res. 2008;1208:234-239.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  de Vasconcelos Dos Santos A, da Costa Reis J, Diaz Paredes B, Moraes L, Jasmin , Giraldi-Guimarães A, Mendez-Otero R. Therapeutic window for treatment of cortical ischemia with bone marrow-derived cells in rats. Brain Res. 2010;1306:149-158.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Jung DI, Ha J, Kang BT, Kim JW, Quan FS, Lee JH, Woo EJ, Park HM. A comparison of autologous and allogenic bone marrow-derived mesenchymal stem cell transplantation in canine spinal cord injury. J Neurol Sci. 2009;285:67-77.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Zhao LR, Duan WM, Reyes M, Keene CD, Verfaillie CM, Low WC. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol. 2002;174:11-20.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M. Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport. 2001;12:559-563.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Hayase M, Kitada M, Wakao S, Itokazu Y, Nozaki K, Hashimoto N, Takagi Y, Dezawa M. Committed neural progenitor cells derived from genetically modified bone marrow stromal cells ameliorate deficits in a rat model of stroke. J Cereb Blood Flow Metab. 2009;29:1409-1420.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Kuh SU, Cho YE, Yoon DH, Kim KN, Ha Y. Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat. Acta Neurochir (Wien). 2005;147:985-92; discussion 992.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Castro RF, Jackson KA, Goodell MA, Robertson CS, Liu H, Shine HD. Failure of bone marrow cells to transdifferentiate into neural cells in vivo. Science. 2002;297:1299.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science. 2002;297:2256-2259.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Roybon L, Ma Z, Asztely F, Fosum A, Jacobsen SE, Brundin P, Li JY. Failure of transdifferentiation of adult hematopoietic stem cells into neurons. Stem Cells. 2006;24:1594-1604.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Coyne TM, Marcus AJ, Woodbury D, Black IB. Marrow stromal cells transplanted to the adult brain are rejected by an inflammatory response and transfer donor labels to host neurons and glia. Stem Cells. 2006;24:2483-2492.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Kim KN, Oh SH, Lee KH, Yoon DH. Effect of human mesenchymal stem cell transplantation combined with growth factor infusion in the repair of injured spinal cord. Acta Neurochir Suppl. 2006;99:133-136.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Hunt DP, Irvine KA, Webber DJ, Compston DA, Blakemore WF, Chandran S. Effects of direct transplantation of multipotent mesenchymal stromal/stem cells into the demyelinated spinal cord. Cell Transplant. 2008;17:865-873.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Barnabé GF, Schwindt TT, Calcagnotto ME, Motta FL, Martinez G Jr, de Oliveira AC, Keim LM, D'Almeida V, Mendez-Otero R, Mello LE. Chemically-induced RAT mesenchymal stem cells adopt molecular properties of neuronal-like cells but do not have basic neuronal functional properties. PLoS One. 2009;4:e5222.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Raedt R, Pinxteren J, Van Dycke A, Waeytens A, Craeye D, Timmermans F, Vonck K, Vandekerckhove B, Plum J, Boon P. Differentiation assays of bone marrow-derived Multipotent Adult Progenitor Cell (MAPC)-like cells towards neural cells cannot depend on morphology and a limited set of neural markers. Exp Neurol. 2007;203:542-554.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Harting MT, Jimenez F, Adams SD, Mercer DW, Cox CS Jr. Acute, regional inflammatory response after traumatic brain injury: Implications for cellular therapy. Surgery. 2008;144:803-813.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815-1822.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Walker PA, Harting MT, Jimenez F, Shah SK, Pati S, Dash PK, Cox CS Jr. Direct intrathecal implantation of mesenchymal stromal cells leads to enhanced neuroprotection via an NFkappaB-mediated increase in interleukin-6 production. Stem Cells Dev. 2010;19:867-876.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Liu N, Chen R, Du H, Wang J, Zhang Y, Wen J. Expression of IL-10 and TNF-alpha in rats with cerebral infarction after transplantation with mesenchymal stem cells. Cell Mol Immunol. 2009;6:207-213.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, Martinello M, Cattalini A, Bergami A, Furlan R. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature. 2005;436:266-271.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS Jr. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009;18:683-692.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Harting MT, Jimenez F, Xue H, Fischer UM, Baumgartner J, Dash PK, Cox CS. Intravenous mesenchymal stem cell therapy for traumatic brain injury. J Neurosurg. 2009;110:1189-1197.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Semprun-Prieto L, Delafontaine P, Prockop DJ. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009;5:54-63.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Lu D, Sanberg PR, Mahmood A, Li Y, Wang L, Sanchez-Ramos J, Chopp M. Intravenous administration of human umbilical cord blood reduces neurological deficit in the rat after traumatic brain injury. Cell Transplant. 2002;11:275-281.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Mahmood A, Lu D, Chopp M. Intravenous administration of marrow stromal cells (MSCs) increases the expression of growth factors in rat brain after traumatic brain injury. J Neurotrauma. 2004;21:33-39.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Mei SH, McCarter SD, Deng Y, Parker CH, Liles WC, Stewart DJ. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. 2007;4:e269.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol. 1993;11:165-190.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Bonder CS, Norman MU, Macrae T, Mangan PR, Weaver CT, Bullard DC, McCafferty DM, Kubes P. P-selectin can support both Th1 and Th2 lymphocyte rolling in the intestinal microvasculature. Am J Pathol. 2005;167:1647-1660.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Hernandez LA, Grisham MB, Twohig B, Arfors KE, Harlan JM, Granger DN. Role of neutrophils in ischemia-reperfusion-induced microvascular injury. Am J Physiol. 1987;253:H699-703.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15:42-49.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Ajmo CT Jr, Collier LA, Leonardo CC, Hall AA, Green SM, Womble TA, Cuevas J, Willing AE, Pennypacker KR. Blockade of adrenoreceptors inhibits the splenic response to stroke. Exp Neurol. 2009;218:47-55.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Vendrame M, Gemma C, Pennypacker KR, Bickford PC, Davis Sanberg C, Sanberg PR, Willing AE. Cord blood rescues stroke-induced changes in splenocyte phenotype and function. Exp Neurol. 2006;199:191-200.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Schwarting S, Litwak S, Hao W, Bähr M, Weise J, Neumann H. Hematopoietic stem cells reduce postischemic inflammation and ameliorate ischemic brain injury. Stroke. 2008;39:2867-2875.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Lee ST, Chu K, Jung KH, Kim SJ, Kim DH, Kang KM, Hong NH, Kim JH, Ban JJ, Park HK. Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. Brain. 2008;131:616-629.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood. 2005;106:1755-1761.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Kassis I, Grigoriadis N, Gowda-Kurkalli B, Mizrachi-Kol R, Ben-Hur T, Slavin S, Abramsky O, Karussis D. Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis. Arch Neurol. 2008;65:753-761.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Rafei M, Campeau PM, Aguilar-Mahecha A, Buchanan M, Williams P, Birman E, Yuan S, Young YK, Boivin MN, Forner K. Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. J Immunol. 2009;182:5994-6002.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Yoon JK, Park BN, Shim WY, Shin JY, Lee G, Ahn YH. In vivo tracking of 111In-labeled bone marrow mesenchymal stem cells in acute brain trauma model. Nucl Med Biol. 2010;37:381-388.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Detante O, Moisan A, Dimastromatteo J, Richard MJ, Riou L, Grillon E, Barbier E, Desruet MD, De Fraipont F, Segebarth C. Intravenous administration of 99mTc-HMPAO-labeled human mesenchymal stem cells after stroke: in vivo imaging and biodistribution. Cell Transplant. 2009;18:1369-1379.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Vilalta M, Dégano IR, Bagó J, Gould D, Santos M, García-Arranz M, Ayats R, Fuster C, Chernajovsky Y, García-Olmo D. Biodistribution, long-term survival, and safety of human adipose tissue-derived mesenchymal stem cells transplanted in nude mice by high sensitivity non-invasive bioluminescence imaging. Stem Cells Dev. 2008;17:993-1003.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Kang SK, Shin MJ, Jung JS, Kim YG, Kim CH. Autologous adipose tissue-derived stromal cells for treatment of spinal cord injury. Stem Cells Dev. 2006;15:583-594.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS Jr. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009;18:683-692.  [PubMed]  [DOI]  [Cited in This Article: ]