Printer Friendly

In Vivo Assessment of Stem Cells for Treating Neurodegenerative Disease: Current Approaches and Future Prospects.

1. Introduction

Stem cell therapy is an emerging strategy to directly restore neural function and synaptic circuit in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD) [1]. Many progressive therapies have been developed to reduce neuronal loss and neurological impairment through cellular replacement and other cell-based treatments, including cell culture media and extracellular vesicles [2-4]. Although stem cell research has been undertaken in a disease-specific manner, there are few currently available treatments that have applications in clinical reality. The key difficulty in achieving clinical success with stem cell therapy is the precise evaluation of the status of the transplanted cells and the condition of graft-host cells in vivo. There is an urgent need for improvement and development of noninvasive technologies for assessing the efficacy of proof-of-concept (PoC) therapy in vivo [5]. Here we review representative reports in terms of in vivo stem cell PoC therapy. In detail, we explain cell survival, therapeutic efficacy, and functional mechanisms after stem cell transplantation. We highlight the application of emerging technologies, which effectively validate in vivo PoC therapies for treating neurodegenerative diseases.

2. Stem Cell Tracking

In damaged brain tissue at the site of neurodegenerative disease, molecular mechanisms, synapses, neuronal subpopulations, and neural networks can be altered compared to those in normal brain tissue [6]. There are a number of major issues in carrying out assessment of PoC stem cell transplantation in vivo in these cases. First, it is necessary to analyze the efficiency and efficacy of adherent or surviving cells as compared to those of the grafted cells. Cerri et al. carried out intracarotid infusion of mesenchymal stem cells (MSCs) in a 6-hydroxydopamine (6-OHDA) rat model of PD. After a transient blood-brain barrier (BBB) opening with mannitol, MSC distribution was quantitatively analyzed 7 and 28 days after infusion. To analyze the pattern of cell distribution, colabeling with CellVue NIR815 and PKH26 differentiated infused MSCs preferentially localized in both contralateral and ipsilateral hemispheres. MSCs were more than 9.9% alive in the striatum and substantia nigra pars compacta (SNc) compared to other brain areas at 28 days [7]. Second, specific migration of transplanted cells in situ is important at the site of injury. Anderson and Caldwell reported extensive migration of human neural progenitor cells (HNPCs) when grafted into the subthalamic nucleus. Using a human-specific nuclear marker (hNuc) and a doublecortin (DCX) antibody associated with neuroblast migration, researchers could confirm that HNPCs remain in an immature state [8]. Third, it is important to determine how engrafted cells function. Gubert et al. investigated the fate of transplanted bone-marrow mononuclear cells (BMMCs) in a mouse model of amyotrophic lateral sclerosis (ALS) (SOD1G93A mice). Using the fluorescent cell marker CellTrace[TM] and superparamagnetic iron nanoparticles (SPION) FeraTrack[TM], researchers verified that BMMCs interact with microglial phagocyte profiles in the lumbar spinal cord. BMMC therapy resulted in a mild temporary effect in the presymptomatic phase of ALS [9]. Finally, mapping of cell spatial distribution and connectivity in the graft-host area is important, because it allows for specific analysis of micro-environmental change brought about by stem cell therapy. Grealish et al. used a modified rabies virus to trace afferent and efferent connectivity of engrafted human embryonic stem cell- (hESC-) derived dopaminergic neurons. They found that transplanted dopaminergic neurons were integrated into the host neural circuitry in a rat model of PD [10]. This study demonstrates that special image tracing technology can convey intrastriatal graft-host connectivity in stem cell-based therapy and can easily be applied to analyze different neuronal subtypes.

To solve these problems for the assessment of in vivo PoC stem cell therapy, many histological and imaging techniques have been developed. Specific proteins, DNA/RNAconjugated fluorescent dyes, and viral/nonviral constructs have been used to label stem cells before therapy and then used for visualization and tracking of implanted cells in vivo, using imaging modalities including magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and near-infrared (NIR) fluorophores. Recently developed tracking and imaging techniques provide more detailed analysis of cellular phenotypes and functional analysis in stem cell therapy.

2.1. Cell Labeling

2.1.1. Histochemical Analysis. In general, thymidine analogues have been used to detect proliferative stem cells. The thymidine analogue is a synthetic nucleoside that becomes incorporated into newly dividing DNA. Cells are treated with thymidine analogues such as bromodeoxyuridine (BrdU) to directly track transplanted stem cells. In traumatic brain injury (TBI) known as delayed-onset neurodegenerative syndrome, MSCs cultured with neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), were labeled with BrdU. Eight days after TBI, these cells were found in the injected and injured sites [11]. In another study, the sphere derived from human neural stem/progenitor cells was labeled with a pulse of 10 [micro]M BruU before transplantation. After 2 or 6 weeks following implantation, engrafted spheres were found in the perilesional zone, hippocampus, corpus callosum, and ipsilateral subependymal zone of rat brains. Furthermore, at 6 weeks, stem cells had migrated and differentiated in the contralateral cortex [12]. Wennersten et al. used intraperitoneally applied BrdU for detecting endogenous stem cells or tracing cell lineage in newborns. At 2 and 4 weeks after transplantation, the number of BrdU-positive cells had increased in the hippocampus of human MSC-injected animals compared to that in AD animals, which were at normal levels. In the dentate gyrus of brains, the number of BrdU-positive cells stained with Hud (ELAV-like protein 4, ELAVL4) were also considerably elevated in the MSC-treated group (73.3% of BrdU-positive cells) compared to that in normal mice (45%). This suggests that BrdU- or BrdU/HuD-staining is a meaningful method for the detection and assessment of endogenous adult neurogenesis after MSC administration for AD treatment [13].

Using a Huntington's disease model induced by unilateral intrastriatal administration of quinolinic acid, rats received human immortalized neural stem-like cells (NSCs) infected with vector encoding [beta]-galactosidase (lac Z). The reporter gene fuses with an intracellular promoter, and its activity is approximately the same as the steady-state mRNA level. Transplanted cells were labeled with X-gal to identify the lac Z-stained region, and migrated NSCs were found in the striatum of rats at 2 weeks after an intravenous injection of cells [14].

For long-term tracking of injected stem cells, researchers have applied fluorescent in situ hybridization (FISH). In an adult female intracerebral hemorrhage model, male MSCs were injected into the striatum, and then FISH was carried out with double staining of the chromosomal Y-linked SrY-gene and neuronal nuclei (NeuN) protein or gliofibrillary acidic protein (GFAP). After 2 months, histological analysis of graft-host integration and phenotypic expression of GFAP and NeuN was carried out [15]. In severe TBI, Sry-positive MSCs were identified by FISH analysis of colabeled with NeuN or GFAP [16].

2.1.2. Fluorescent Assay. Fluorescent labels have been used to analyze the efficacy of stem cell therapy in many cases because of their ease of handling and ability to penetrate cells. Their use can be divided into three categories, according to technique and characteristics. The first of these involves applying a membrane dye that stains the cell surface, including lipophilic compounds [17]. Mouse ESCs labeled with a yellow-orange fluorescent dye with long aliphatic tails (PKH26, Sigma-Aldrich) were transplanted in the striatum in 6-OHDA-lesioned rats. At 4 weeks, ESCs were directly visualized with PKH26 costained tyrosine-hydroxylase (TH), not tumor growth [18]. Sadan et al. confirmed that, in the quinolinic acid-induced striatal lesion model for HD, MSCs secreting neurotrophic factors had migrated to adjacent sections of the risk area, by staining injected cells with PKH26 and host macrophages with macrophage marker ED1 (CD68). About 23.07 [+ or -] 7.91% of the total surviving injected cells were phagocytosed by host macrophage at site [19]. In another study, the Vybrant[R] series (DiO, Dil, and DiD, ThermoFisher Scientific) lipophilic carbocyanine-based dyes were used to trackstem cells. With 2 [micro]g/mL of CM-DiI, MSCs were labeled and transplanted into the right cerebellar hemisphere (folia VI). After 6 weeks, DiI-labeled MSCs were found surviving and migrating in a deep layer of the cerebellar cortex [20]. Lee et al. transplanted adipose-derived stem cells (ASCs) labeled with Vybrant DiO and costained with specific antibodies including those against BDNF, calbindin, [gamma]-amino butyric acid (GABA), and glutamic acid decarboxylase (GAD). In addition, they infected ASCs with virus carrying green fluorescent protein (GFP) and then implanted these in a HD model. Through these processes, the level of ASCs was doubly verified in vivo [21].

GFP-producing animals are a fundamental cell tracking tool. Various stem cells harvested from GFP-transgenic animals have been used to study neurodegenerative disease. In 2015, Hoban et al. reported functional improvement of glial cell line-derived neurotrophic factor (GDNF) induced MSCs in the lipopolysaccharide (LPS) inflammatory model of PD. Twenty-one days after transplantation, only 40% of transplanted MSCs had survived [22]. GFP-producing MSCs, macrophages, and microglia were delivered to the brain of PD and AD model mice by intranasal application. Seven days after application, labeled MSCs were found in the olfactory bulb and brain stem of (Thy1)-h[A30P] [alpha]S and APP/PS1 transgenic mice [23].

Sibov et al. demonstrated multimodal activity of iron oxide nanoparticles linked with Rhodamine-B (MION-Rh, BioPAL Inc.) in umbilical cord blood (UC-) MSCs therapy. They found that UC-MSCs labeled with MION-Rh were detectable by MRI in an animal model of PD. These cells slowly migrated from the medial forebrain bundle to the substantia nigra, where they were detected by T2 MRI as hypointense spots [24].

2.2. Imaging Technology. Researchers need to be able to identify stem cells in vivo at the cellular and molecular level for tracking and assessing therapeutic efficacy. Noninvasive imaging techniques enable researchers to understand the exact in vivo stem cell therapy PoC in neurodegenerative disease. Here we review the specific imaging techniques and the future goals for clinical study.

2.2.1. MRI and PET. Among noninvasive techniques, MRI provides the highest spatial resolution for acquiring cellular and molecular images. Modo et al. performed MRI to track engrafted stem cells in an animal study of brain disease for the first time [25]. Owing to significant T2 effect, iron nanoparticles have been used in stem cell tracking instead of gadolinium-based particles [26]. HNPCs overexpressing ferritin, an iron storage protein, were found in the striatum of rat brains by MRI. Furthermore, hypointensity was increased in SPION-labeled HNPCs [27]. In studying the migratory process of neurotrophic factors-secreting MSCs, MRI was also used for high-resolution 2D and 3D imaging in HD [19]. In TBI therapy, HNPCs treated with ultrasmall SPION (USPION) and/or Molday ION Rhodamine-B (MIRB[TM]) had been identified with increased homing and retention, using 0.6T MRI [28]. Furthermore, MRI has been used to assess a diagnostic strategy by finding common biomarkers of AD after stem cell transplantation [29].

PET in combination with MRI can provide information on importance of in vivo PoC parameters, including optimal cell dose, cell tracking, graft volume, and functional assessment [30]. To define a preclinical assessment, Grealish et al. reported long-term survival of hESC-derived midbrain dopamine neurons in a rat PD model. Using MRI and PET imaging techniques, the striatal dopaminergic neurotransmission ([sup.18]F-fallypride as [D.sub.2]/[D.sub.3]-receptor occupancy) and thedopaminetransporter (DAT, [sup.18]F-LBT999 as a tracer) were assessed [31].

2.2.2. SPECT and NIR. SPECT is a nuclear tomographic imaging technique that uses a gamma ray camera. In hemiparkinsonian rhesus monkeys, dopaminergic function was measured by DAT activity in a MSC-derived dopaminergic neuron-like cell-transplanted brain [32]. Furthermore, it is suggested that [[sup.123]I]-2[beta]-carbomethoxy-3[beta]-(4-fluorophenyl)- N-(3-iodo-E-allyl)nortropane ([[sup.123]I]altropane) can be used to identify DAT. This suggests that SPECT-[[sup.123]I]altropane is a specific marker to measure dopaminergic content for functional verification [33].

Near-infrared light (NIR) imaging has the advantage of noninvasive detection, while being capable of penetrating deep into tissues. Human MSCs were detected and quantified using CellVue[R] NIR815 and NIR scanning to render contour, reconstruction, and coronal section at the cell-engrafted site in 3D. Finally, NIR815-hMSC localization was measured in vivo over time [34].

3. Future Directions

An important development in assessing stem cell therapy with brain imaging is the ability to measure the relationship and connectivity between graft and host cells in 3D. The CLARITY (Clear, Lipid-exchanged, Acrylamide-hybridized Rigid, Imaging/immunostaining compatible, Tissue hYdrogel) method is the best currently available tool for analyzing graft-host relationships between stem cells and diseased tissue. This technique was first developed by Karl Deisseroth from Stanford University [35]. For building hydrogel-tissue hybridization structures, a hydrogel monomer is infused into whole brain tissue. SDS micelle then captures lipids in the tissue, which leads to tissue transparency during electrophoresis. Stem cells are labeled with specific dyes before the animals are killed and the clear tissue is then immunostained. Data is acquired by confocal, two-photon, or light-sheet microscopy and analyzed by 3D rendering software. Other tissue clearing techniques are ACT-PRESTO (active clarity technique-pressure related efficient and stable transfer of macromolecules into organs) [36], PACT (passive clarity technique) [37], and uDISCO (ultimate 3D imaging of solvent-cleared organs) [38].

In this review, conventional stem cell tracking and assessing techniques have been discussed, including noninvasive imaging methods. This review has demonstrated that these techniques can help the assessment of in vivo PoC stem cell therapy and thus serve as the basis for clinical monitoring of neurodegenerative disease.

http://dx.doi.org/ 10.1155/2017/9751583

Competing Interests

The authors declare that they have no conflict of interests.

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2015R1C1A1A02037693).

References

[1] O. Lindvall, Z. Kokaia, and A. Martinez-Serrano, "Stem cell therapy for human neurodegenerative disorders--how to make it work," Nature Medicine, vol. 10, pp. S42-S50, 2004.

[2] M. Yang, N. D. Stull, M. A. Berk, E. Y. Snyder, and L. Iacovitti, "Neural stem cells spontaneously express dopaminergic traits after transplantation into the intact or 6-hydroxydopaminelesioned rat," Experimental Neurology, vol. 177, no. 1, pp. 50-60, 2002.

[3] L. Crigler, R. C. Robey, A. Asawachaicharn, D. Gaupp, and D. G. Phinney, "Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis," Experimental Neurology, vol. 198, no. 1, pp. 54-64, 2006.

[4] A. Jarmalaviciute, V. Tunaitis, U. Pivoraite, A. Venalis, and A. Pivoriunas, "Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamineinduced apoptosis," Cytotherapy, vol. 17, no. 7, pp. 932-939, 2015.

[5] K. Bhakoo, "In vivo stem cell tracking in neurodegenerative therapies," Expert Opinion on Biological Therapy, vol. 11, no. 7, pp. 911-920, 2011.

[6] Y.-C. Hsu, S.-L. Chen, D.-Y. Wang, and I.-M. Chiu, "Stem cell-based therapy in neural repair," Biomedical Journal, vol. 36, no. 3, pp. 98-105, 2013.

[7] S. Cerri, R. Greco, G. Levandis et al., "Intracarotid infusion of mesenchymal stem cells in an animal model of Parkinson's disease, focusing on cell distribution and neuroprotective and behavioral effects," Stem Cells Translational Medicine, vol. 4, no. 9, pp. 1073-1085, 2015.

[8] L. Anderson and M. A. Caldwell, "Human neural progenitor cell transplants into the subthalamic nucleus lead to functional recovery in a rat model of Parkinson's disease," Neurobiology of Disease, vol. 27, no. 2, pp. 133-140, 2007.

[9] F. Gubert, A. B. Decotelli, I. Bonacossa-Pereira et al., "Intraspinal bone-marrow cell therapy at pre- and symptomatic phases in a mouse model of amyotrophic lateral sclerosis," Stem Cell Research and Therapy, vol. 7, article no. 41, 2016.

[10] S. Grealish, A. Heuer, T. Cardoso et al., "Monosynaptic tracing using modified rabies virus reveals early and extensive circuit integration of human embryonic stem cell-derived neurons," Stem Cell Reports, vol. 4, no. 6, pp. 975-983, 2015.

[11] A. Mahmood, D. Lu, L. Wang, and M. Chopp, "Intracerebral transplantation of marrow stromal cells cultured with neurotrophic factors promotes functional recovery in adult rats subjected to traumatic brain injury," Journal of Neurotrauma, vol. 19, no. 12, pp. 1609-1617, 2002.

[12] A. Wennersten, X. Meijer, S. Holmin, L. Wahlberg, and T. Mathiesen, "Proliferation, migration, and differentiation of human neural stem/progenitor cells after transplantation into a rat model of traumatic brain injury," Journal of Neurosurgery, vol. 100, no. 1, pp. 88-96, 2004.

[13] S. H. Oh, H. N. Kim, H. J. Park, J. Y. Shin, and P. H. Lee, "Mesenchymal stem cells increase hippocampal neurogenesis and neuronal differentiation by enhancing the Wnt signaling pathway in Alzheimer's disease model," Cell Transplantation, vol. 24, no. 6, pp. 1097-1109, 2015.

[14] S.-T. Lee, J.-E. Park, K. Lee et al., "Noninvasive method of immortalized neural stem-like cell transplantation in an experimental model of Huntington's disease," Journal of Neuroscience Methods, vol. 152, no. 1-2, pp. 250-254, 2006.

[15] L. Otero, M. Zurita, C. Bonilla et al., "Late transplantation of allogeneic bone marrow stromal cells improves neurologic deficits subsequent to intracerebral hemorrhage," Cytotherapy, vol. 13, no. 5, pp. 562-571, 2011.

[16] C. Bonilla, M. Zurita, L. Otero, C. Aguayo, and J. Vaquero, "Delayed intralesional transplantation of bone marrow stromal cells increases endogenous neurogenesis and promotes functional recovery after severe traumatic brain injury," Brain Injury, vol. 23, no. 9, pp. 760-769, 2009.

[17] P. K. Wallace, J. D. Tario Jr., J. L. Fisher, S. S. Wallace, M. S. Ernstoff, and K. A. Muirhead, "Tracking antigen-driven responses by flow cytometry: monitoring proliferation by dye dilution," Cytometry Part A, vol. 73, no. 11, pp. 1019-1034, 2008.

[18] P. C. Baier, J. Schindehutte, K. Thinyane et al., "Behavioral changes in unilaterally 6-hydroxy-dopamine lesioned rats after transplantation of differentiated mouse embryonic stem cells without morphological integration," Stem Cells, vol. 22, no. 3, pp. 396-404, 2004.

[19] O. Sadan, N. Shemesh, R. Barzilay et al., "Migration of neurotrophic factors-secreting mesenchymal stem cells toward a quinolinic acid lesion as viewed by magnetic resonance imaging," Stem Cells, vol. 26, no. 10, pp. 2542-2551, 2008.

[20] M. A. Edalatmanesh, A. R. Bahrami, E. Hosseini, M. Hosseini, and S. Khatamsaz, "Neuroprotective effects of mesenchymal stem cell transplantation in animal model of cerebellar degeneration," Neurological Research, vol. 33, no. 9, pp. 913-920, 2011.

[21] S.-T. Lee, K. Chu, K.-H. Jung et al., "Slowed progression in models of Huntington disease by adipose stem cell transplantation," Annals of Neurology, vol. 66, no. 5, pp. 671-681, 2009.

[22] D. B. Hoban, L. Howard, and E. Dowd, "GDNF-secreting mesenchymal stem cells provide localized neuroprotection in an inflammation-driven rat model of Parkinson's disease," Neuroscience, vol. 303, pp. 402-411, 2015.

[23] L. Danielyan, S. Beer-Hammer, A. Stolzing et al., "Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer's and Parkinson's disease," Cell Transplantation, vol. 23, supplement 1, pp. S123-S139, 2014.

[24] T. T. Sibov, L. F. Pavon, L. A. Miyaki et al., "Umbilical cord mesenchymal stem cells labeled with multimodal iron oxide nanoparticles with fluorescent and magnetic properties: application for in vivo cell tracking," International Journal of Nanomedicine, vol. 9, no. 1, pp. 337-350, 2014.

[25] M. Modo, D. Cash, K. Mellodew et al., "Tracking transplanted stem cell migration using bifunctional, contrast agent-enhanced, magnetic resonance imaging," NeuroImage, vol. 17, no. 2, pp. 803-811, 2002.

[26] A. Darkazalli and C. W. Levenson, "Tracking stem cell migration and survival in brain injury: current approaches and future prospects," Histology and Histopathology, vol. 27, no. 10, pp. 1255-1261, 2012.

[27] K. Bernau, C. M. Lewis, A. M. Petelinsek et al., "In vivo tracking of human neural progenitor cells in the rat brain using magnetic resonance imaging is not enhanced by ferritin expression," Cell Transplantation, vol. 25, no. 3, pp. 575-592, 2016.

[28] W.-B. Shen, C. Plachez, O. Tsymbalyuk et al., "Cell-based therapy in TBI: magnetic retention of neural stem cells in vivo," Cell Transplantation, vol. 25, no. 6, pp. 1085-1099, 2016.

[29] A. Luarte, L. F. Batiz, U. Wyneken, and C. Lafourcade, "Potential therapies by stem cell-derived exosomes in CNS diseases: focusing on the neurogenic niche," Stem Cells International, vol. 2016, Article ID 5736059, 16 pages, 2016.

[30] M. Ramos-Gomez and A. Martinez-Serrano, "Tracking of iron-labeled human neural stem cells by magnetic resonance imaging in cell replacement therapy for Parkinson's disease," Neural Regeneration Research, vol. 11, no. 1, pp. 49-52, 2016.

[31] S. Grealish, E. Diguet, A. Kirkeby et al., "Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease," Cell Stem Cell, vol. 15, no. 5, pp. 653-665, 2014.

[32] W.-P. Wang, Z.-L. He, S.-Y. Lu et al., "Dopaminergic neuron-like cells derived from bone marrow mesenchymal stem cells by lmx1a and neurturin overexpression for autologous cytotherapy in hemiparkinsonian rhesus monkeys," Current Stem Cell Research and Therapy, vol. 10, no. 2, pp. 109-120, 2015.

[33] J. A. Gleave, T. H. Farncombe, C. Saab, and L. C. Doering, "Correlative single photon emission computed tomography imaging of [123I]altropane binding in the rat model of Parkinson's," Nuclear Medicine and Biology, vol. 38, no. 5, pp. 741-749, 2011.

[34] P. Bossolasco, L. Cova, G. Levandis et al., "Noninvasive near-infrared live imaging of human adult mesenchymal stem cells transplanted in a rodent model of Parkinson's disease," International Journal of Nanomedicine, vol. 7, pp. 435-437, 2012.

[35] K. Chung, J. Wallace, S.-Y. Kim et al., "Structural and molecular interrogation of intact biological systems," Nature, vol. 497, no. 7449, pp. 332-337, 2013.

[36] E. Lee, J. Choi, Y. Jo et al., "ACT-PRESTO: rapid and consistent tissue clearing and labeling method for 3-dimensional (3D) imaging," Scientific Reports, vol. 6, Article ID 18631, 2016.

[37] B. Yang, J. B. Treweek, R. P. Kulkarni et al., "Single-cell phenotyping within transparent intact tissue through whole-body clearing," Cell, vol. 158, no. 4, pp. 945-958, 2014.

[38] C. Pan, R. Cai, F. P. Quacquarelli et al., "Shrinkage-mediated imaging of entire organs and organisms using uDISCO," Nature Methods, vol. 13, no. 10, pp. 859-867, 2016.

Byeong-Wook Song (1, 2)

(1) EIT/LOFUS R&D Center, Institute for Integrative Medicine, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 25601, Republic of Korea

(2) Catholic Kwandong University International St. Mary's Hospital, 25 Simgok- Ro, 100 Beon-Gil, Seo-Gu, Incheon 22711, Republic of Korea

Correspondence should be addressed to Byeong-Wook Song; songbw@gmail.com

Received 22 November 2016; Accepted 7 February 2017; Published 23 February 2017

Academic Editor: Eva Mezey
COPYRIGHT 2017 COPYRIGHT 2010 SAGE-Hindawi Access to Research
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2017 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Song, Byeong-Wook
Publication:Stem Cells International
Article Type:Report
Date:Jan 1, 2017
Words:3709
Previous Article:Mesenchymal Stromal Cells Accelerate Epithelial Tight Junction Assembly via the AMP-Activated Protein Kinase Pathway, Independently of Liver Kinase...
Next Article:In Vivo Immunogenic Response to Allogeneic Mesenchymal Stem Cells and the Role of Preactivated Mesenchymal Stem Cells Cotransplanted with Allogeneic...
Topics:

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters