Cell Transplantation 24(4) Abstracts

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Cell Transplantation, Vol. 24, pp. 591-597, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687723
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Proposal

No Pain, No Gain: Lack of Exercise Obstructs Neurogenesis

Nate Watson,* Xunming Ji,† Takao Yasuhara,‡ Isao Date,‡ Yuji Kaneko,* Naoki Tajiri,* and Cesar V. Borlongan*

*Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA
†Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
‡Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Bedridden patients develop atrophied muscles, their daily activities greatly reduced, and some display a depressive mood. Patients who are able to receive physical rehabilitation sometimes show surprising clinical improvements, including reduced depression and attenuation of other stress-related behaviors. Regenerative medicine has advanced two major stem cell-based therapies for CNS disorders, namely, transplantation of exogenous stem cells and amplification of endogenous neurogenesis. The latter strategy embraces a natural way of reinnervating the damaged brain and correcting the neurological impairments. In this study, we discussed how immobilization-induced disuse atrophy, using the hindlimb suspension model, affects neurogenesis in rats. The overarching hypothesis is that immobilization suppresses neurogenesis by reducing the circulating growth or trophic factors, such as vascular endothelial growth factor or brain-derived neurotrophic factor. That immobilization alters neurogenesis and stem cell differentiation in the CNS requires characterization of the stem cell microenvironment by examining the trophic and growth factors, as well as stress-related proteins that have been implicated in exercise-induced neurogenesis. Although accumulating evidence has revealed the contribution of “increased” exercise on neurogenesis, the reverse paradigm involving “lack of exercise,” which mimics pathological states (e.g., stroke patients are often immobile), remains underexplored. This novel paradigm will enable us to examine the effects on neurogenesis by a nonpermissive stem cell microenvironment likely produced by lack of exercise. BrdU labeling of proliferative cells, biochemical assays of serum, cerebrospinal fluid and brain levels of trophic factors, growth factors, and stress-related proteins are proposed as indices of neurogenesis, while quantitative measurements of spontaneous movements will reveal psychomotor components of immobilization. Studies designed to reveal how in vivo stimulation, or lack thereof, alters the stem cell microenvironment are needed to begin to develop treatment strategies for enhancing neurogenesis in bedridden patients.

Key words: Stem cells; Immobilization; Neurogenesis; Physical exercise; Neurological disorders

Received February 19, 2015; final acceptance March 9, 2015. Online prepub date: March 24, 2015.
Address correspondence to Dr. Cesar V. Borlongan, MDC 78, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA. Tel: +1-813-974-3154; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 599-612, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687750
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Pathologic Potential of Astrocytic Vesicle Traffic: New Targets to Treat Neurologic Diseases?

Nina Vardjan,*† Alexei Verkhratsky,*†‡§ and Robert Zorec*†

*Celica Biomedical, Ljubljana, Slovenia
†Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
‡Achucarro Center for Neuroscience, Ikerbasque, Basque Foundation for Science, Bilbao, Spain
§Faculty of Life Sciences, The University of Manchester, Manchester, UK

Vesicles are small intracellular organelles that are fundamental for constitutive housekeeping of the plasmalemma, intercellular transport, and cell-to-cell communications. In astroglial cells, traffic of vesicles is associated with cell morphology, which determines the signaling potential and metabolic support for neighboring cells, including when these cells are considered to be used for cell transplantations or for regulating neurogenesis. Moreover, vesicles are used in astrocytes for the release of vesicle-laden chemical messengers. Here we review the properties of membrane-bound vesicles that store gliotransmitters, endolysosomes that are involved in the traffic of plasma membrane receptors, and membrane transporters. These vesicles are all linked to pathological states, including amyotrophic lateral sclerosis, multiple sclerosis, neuroinflammation, trauma, edema, and states in which astrocytes contribute to developmental disorders. In multiple sclerosis, for example, fingolimod, a recently introduced drug, apparently affects vesicle traffic and gliotransmitter release from astrocytes, indicating that this process may well be used as a new pathophysiologic target for the development of new therapies.

Key words: Astrocytes; Glia; Vesicles; Trafficking; Reactive astrogliosis; Morphology; Gliotransmitter; Antigen presentation; Neurogenesis; Neuroinflammation; Amyotrophic lateral sclerosis; Multiple sclerosis

Received January 8, 2015; final acceptance March 9, 2015. Online prepub date: March 24, 2015.
Address correspondence to Robert Zorec, Institute of Pathophysiology, Faculty of Medicine, LN-MCP, Zaloška 4, Ljubljana, SI1000, Slovenia. Tel: +38615437080; Fax: +38615437036; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 613-623, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687778
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Roles of Kinins in the Nervous System

Priscilla D. Negraes,* Cleber A. Trujillo,† Micheli M. Pillat,* Yang D. Teng,‡ and Henning Ulrich*

*Departamento de Bioquimica, Instituto de Quimica, Universidade de Sao Paulo, Sao Paulo, Brazil
†University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children’s Hospital San Diego, Stem Cell Program, La Jolla, CA, USA
‡Departments of Neurosurgery and Physical Medicine and Rehabilitation, Harvard Medical School and Division of SCI Research, VABHS, Boston, MA, USA

The kallikrein–kinin system (KKS) is an endogenous pathway involved in many biological processes. Although primarily related to blood pressure control and inflammation, its activation goes beyond these effects. Neurogenesis and neuroprotection might be stimulated by bradykinin being of great interest for clinical applications following brain injury. This peptide is also an important player in spinal cord injury pathophysiology and recovery, in which bradykinin receptor blockers represent substantial therapeutic potential. Here, we highlight the participation of kinin receptors and especially bradykinin in mediating ischemia pathophysiology in the central and peripheral nervous systems. Moreover, we explore the recent advances on mechanistic and therapeutic targets for biological, pathological, and neural repair processes involving kinins.

Key words: Bradykinin; B1BKR and B2BKR; Neural differentiation; Neuroprotection; Inflammation

Received January 19, 2015; final acceptance March 9, 2015. Online prepub date: March 24, 2015.
Address correspondence to Henning Ulrich, Departamento de Bioquimica, Instituto de Quimica Universidade de Sao Paulo, Av. Prof. Lineu Prestes 748, Sao Paulo 05508-900, Brazil. Tel: +55-11-3091-8512; Fax: +55-11-3815-5579; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 625-630, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X685096
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Bone Marrow-Derived Stem Cell Therapy for Metastatic Brain Cancers

Yuji Kaneko,* Naoki Tajiri,* Meaghan Staples,* Stephanny Reyes,* Diego Lozano,* Paul R. Sanberg,* Thomas B. Freeman,* Harry van Loveren,* Seung U. Kim,† and Cesar V. Borlongan*

*Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA
†Department of Neurology, University of British Columbia, Vancouver, Canada

We propose that stem cell therapy may be a potent treatment for metastatic melanoma in the brain. Here we discuss the key role of a leaky blood–brain barrier (BBB) that accompanies the development of brain metastases. We review the need to characterize the immunological and inflammatory responses associated with tumor-derived BBB damage in order to reveal the contribution of this brain pathological alteration to the formation and growth of brain metastatic cancers. Next, we discuss the potential repair of the BBB and attenuation of brain metastasis through transplantation of bone marrow-derived mesenchymal stem cells with the endothelial progenitor cell phenotype. In particular, we review the need for evaluation of the efficacy of stem cell therapy in repairing a disrupted BBB in an effort to reduce neuroinflammation, eventually attenuating brain metastatic cancers. The demonstration of BBB repair through augmented angiogenesis and vasculogenesis will be critical to establishing the potential of stem cell therapy for the treatment/prevention of metastatic brain tumors. The overarching hypothesis we advanced here is that BBB breakdown is closely associated with brain metastatic cancers of melanoma, exacerbating the inflammatory response of the brain during metastasis, and ultimately worsening the outcome of metastatic brain cancers. Abrogating this leaky BBB-mediated inflammation via stem cell therapy represents a paradigm-shifting approach to treating brain cancer. This review article discusses the pros and cons of cell therapy for melanoma brain metastases.

Key words: Brain tumor; Stem cells; Transplantation; Gene therapy

Received May 8, 2014; final acceptance September 20, 2014. Online prepub date: October 10, 2014.
Address correspondence to Professor Cesar V. Borlongan, Ph.D., Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA. Tel: +1-813-974-3154; Fax: +1-813-974-3078; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 631-644, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687787
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Paracrine Effects of Mesenchymal Stem Cells Induce Senescence and Differentiation of Glioblastoma Stem-Like Cells

Katja Kološa,* Helena Motaln,* Christel Herold-Mende,† Marjan Koršicˇ,‡ and Tamara T. Lah*§

*Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
†Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany
‡Department of Neurosurgery, University Medical Centre of Ljubljana, Ljubljana, Slovenia
§Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia

Glioblastoma multiforme (GBM) displays high resistance to radiation and chemotherapy, due to the presence of a fraction of GBM stem-like cells (GSLCs), which are thus representing the target for GBM elimination. Since mesenchymal stem cells (MSCs) display high tumor tropism, we examined possible antitumor effects of the secreted factors from human MSCs on four GSLC lines (NCH421k, NCH644, NIB26, and NIB50). We found that conditioned media from bone marrow and umbilical cord-derived MSCs (MSC-CM) mediated cell cycle arrest of GSLCs by downregulating cyclin D1. PCR arrays revealed significantly deregulated expression of 13 genes associated with senescence in NCH421k cells exposed to MSC-CM. Among these, ATM, CD44, COL1A1, MORC3, NOX4, CDKN1A, IGFBP5, and SERPINE1 genes were upregulated, whereas IGFBP3, CDKN2A, CITED2, FN1, and PRKCD genes were found to be downregulated. Pathway analyses in GO and KEGG revealed their association with p53 signaling, which can trigger senescence via cell cycle inhibitors p21 or p16. For both, upregulated expression was proven in all four GSLC lines exhibiting senescence after MSC-CM exposure. Moreover, MSC paracrine signals were shown to increase the sensitivity of NCH421k and NCH644 cells toward temozolomide, possibly by altering them toward more differentiated cell types, as evidenced by vimentin and GFAP upregulation, and Sox-2 and Notch-1 downregulation. Our findings support the notion that MSCs possess an intrinsic ability to inhibit cell cycle and induce senescence and differentiation of GSLCs.

Key words: Cell differentiation; Glioblastoma multiforme (GBM); Stem-like cancer cells; Mesenchymal stem cells (MSCs); Senescence; Therapy response

Received January 27, 2015; final acceptance March 9, 2015. Online prepub date: March 24, 2015.
Address correspondence to Dr. Helena Motaln, National Institute of Biology, Department of Genetic Toxicology and Cancer Biology, Večna pot 111, SI-1000 Ljubljana, Slovenia. Tel: +386 5923 2870; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 645-659, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687561
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Stemness Enhancement of Human Neural Stem Cells Following Bone Marrow MSC Coculture

Hariprakash Haragopal,*† Dou Yu,*† Xiang Zeng,*† Soo-Woo Kim,*‡ In-Bo Han,*†1 Alexander E. Ropper,*† Jamie E. Anderson,*† and Yang D. Teng*†§

*Department of Neurosurgery, Harvard Medical School and the Brigham and Women’s Hospital, Boston, MA, USA
†Division of Spinal Cord Injury Research, Veteran Affairs Boston Healthcare System, Boston, MA, USA
‡Division of Periodontology, Harvard Medical School of Dental Medicine, Boston, MA, USA
§Department of Physical Medicine and Rehabilitation, Harvard Medical School and the Spaulding Rehabilitation Hospital, Boston, MA, USA

Rapid loss of stemness capacity in purified prototype neural stem cells (NSCs) remains a serious challenge to basic and clinical studies aiming to repair the central nervous system. Based on the essential role of mesodermal guidance in the process ofneurulation, we hypothesized that coculture of human NSCs (hNSCs) with human bone marrow-derived mesenchymal stromal stem cells (hMSCs) could enhance the stemness of hNSCs through Notch-1 signaling. We have now tested the hypothesis by assessing behaviors of hNSCs and hMSCs under systematically designed coculture conditions relative to monocultures, with or without Notch-1 manipulation in vitro. Our data demonstrate that expression levels of Notch-1 and Hes-1 as determined by immunocytochemistry are significantly higher in hNSCs cocultured with hMSCs than those of controls. Furthermore, coculturing significantly increases immunoreactivity of CD15, a neural stemness marker, but decreases CD24, a marker of neural/neuronal commitment in hNSCs. The effect is independent from the physical status of cell growth since coculture and notch signaling actually promotes hNSC adhesion. Importantly, coculture with hMSCs markedly augments hNSC proliferation rate (e.g., higher yield in G2/M phase subpopulation in a notch-dependent manner detected by flow cytometry) without diminishing their lineage differentiation capabilities. The results suggest that coculture of hNSCs with hMSCs enhances stemness biology of hNSCs partially via activation of Notch-1 signal transduction. Our finding sheds new light on mesoderm–ectoderm cell fate determination via contact-based hMSC–hNSC interactions and provides mechanistic leads for devising effective regimens to sustain and augment stemnessof in vitro established hNSC and hMSC lines for basic science, translational and clinical applications.

Key words: Coculture; Differentiation; Hes-1; Human; Mesenchymal stromal stem cells (MSCs); Neural stem cells (NSCs); Notch-1; Stemness

Received December 23, 2014; final acceptance February 20, 2015. Online prepub date: February 24, 2015.
1Current address: Department of Neurosurgery, CHA University and Cha Bundang Medical Center, Gyeonggi-do, Korea. Address correspondence to Yang D. Teng, Department of Neurosurgery, Harvard Medical School and the Brigham and Women’s Hospital, Boston, MA 02115, USA. E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 661-672, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687796
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Continuous Improvement After Multiple Mesenchymal Stem Cell Transplantations in a Patient With Complete Spinal Cord Injury

Danuta Jarocha,*1 Olga Milczarek,†1 Anna Wedrychowicz,‡ Stanislaw Kwiatkowski,† and Marcin Majka*

*Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Cracow, Poland
†Department of Children Surgery, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Cracow, Poland
‡Department of Pediatric and Adolescent Endocrinology, Jagiellonian University Medical College, Cracow, Poland

Interruption of spinal cord (SC) continuity leads to functional loss below the lesion level. The purpose of this study was to evaluate the safety and efficacy of bone marrow nucleated cell (BMNC) and multiple mesenchymal stem cell (MSC) transplantations in spinal cord injury (SCI). A patient with total SC interruption at the Th2–3 level underwent experimental therapy with BMNC and MSC transplantations followed with intensive neurorehabilitation treatment. At admission, 6 h after SCI, the patient was scored ASIA A, had a Th1 sensation level, paraplegia with sphincter palsy, and was without the ability to control trunk movement. Neurophysiology examination showed bilateral axonal damage to the motor and sensory neural fibers with no motor unit potentials or peripheral motor nerve conduction in the lower extremities. The standard therapy had been applied and had not produced any positive results. The patient was treated with autologous BMNCs injected intravenously (3.2 × 109) and intrathecally (0.5 × 109) 10 weeks after the SCI and with five rounds of MSCs every 3–4 months (1.3–3.65 × 107) administered via lumbar puncture. Total number of transplanted MSC cells during the course of treatment was 1.54 × 108. There were no complications related to transplantations and no side effects related to the therapy during 2 years of treatment. The ASIA score improved from A to C/D (from 112 to 231 points). The sensation level expanded from Th1 to L3–4, and the patient’s ability to control the body trunk was fully restored. Bladder filling sensation, bladder control, and anal sensation were also restored. Muscle strength in the left lower extremities improved from plegia to deep paresis (1 on the Lovett scale). The patient’s ability to move lower extremities against gravity supported by the movements in quadriceps was restored. The patient gained the ability to stand in a standing frame and was able to walk with the support of hip and knee ortheses. Magnetic resonance imaging (MRI) revealed that at the Th2/Th3 level, where the hemorrhagic necrosis was initially observed, small tissue structures appeared. Our results suggest that repeated intrathecal infusions of MSCs might have the potential to produce clinically meaningful improvements for SCI patients.

Key words: Mesenchymal stem cells (MSCs); Spinal cord injury (SCI); Transplantation; Cell therapy

Received October 28, 2014; final acceptance March 13, 2015. Online prepub date: March 24, 2015.
1These authors provided equal contribution to this work.
Address correspondence to Marcin Majka, Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University, Wielicka Street 265, 30-663 Cracow, Poland. Tel: +48 12 659-1593; Fax: + 48 12-659-1594; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 673-680, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687741
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

A Potential Compensatory Role for Endogenous Striatal Tyrosine Hydroxylase-Positive Neurons in a Nonhuman Primate Model of Parkinson’s Disease

Andrew N. Bubak,* D. Eugene Redmond, Jr.,† John D. Elsworth,‡ Robert H. Roth,‡ Timothy J. Collier,§ Kimberly B. Bjugstad,¶ Barbara C. Blanchard,# and John R. Sladek, Jr.#

*Neuroscience Program, University of Colorado-Denver Anschutz Medical Campus, Denver, CO, USA
†Psychiatry and Neurosurgery, Yale University School of Medicine, New Haven, CT, USA
‡Psychiatry, Yale University School of Medicine, New Haven, CT, USA
§Translational Science and Molecular Medicine, Michigan State University, East Lansing, MI, USA
¶Department of Medicine, University of Colorado-Denver Anschutz Medical Campus, Denver, CO, USA
#Neurology and Pediatrics, University of Colorado-Denver Anschutz Medical Campus, Denver, CO, USA

The possibility of enhancing endogenous brain repair following neurological disorders, such as Parkinson’s disease (PD), is of considerable recent interest. One such mechanism may exist in the striatum as an upregulated population of tyrosine hydroxylase (TH)-immunoreactive neurons that appear after 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) lesions in nonhuman primates as well as in humans with PD. An intriguing possibility is that these endogenous neurons reflect a compensatory mechanism to mitigate the loss of striatal DA due to progressive destruction of the nigrostriatal pathway. The possibility of enhancing the number and function of this population is attractive; however, it is crucial to gain further information about these cells in order to comprehend more fully their possible therapeutic potential. The current research was designed to investigate the fate of this endogenous population in African green monkeys rendered parkinsonian by MPTP lesions. Specifically, we assessed changes in the numbers of striatal neurons expressing TH at differing stages of the toxin-induced behavioral disability and discovered a close relationship with symptom severity and striatal DA neuron numbers. Increased numbers of striatal TH-positive neurons were associated with MPTP treatment that produced parkinsonian symptoms compared to numbers of these neurons in MPTP-treated asymptomatic animals and untreated controls. Expression of striatal DA neurons peaked at the manifestation of symptoms in mild/moderate animals and remained stable in animals that were severely parkinsonian. Furthermore, in severely debilitated animals that improved after fetal dopaminergic grafts, we discovered a return to control levels of the endogenous population. Taken together, our results further support the concept that this population of DA neurons responds to variations in striatal DA tone and may serve as a compensatory mechanism to restore striatal DA levels in the context of significant depletion. Artificially manipulating this endogenous population could prove beneficial for PD treatment, especially for individuals in early disease stages.

Key words: Parkinson’s disease; MPTP; Caudate nucleus; Tyrosine hydroxylase (TH); Primate; Compensatory mechanism; Dopamine

Received January 8, 2015; final acceptance March 9, 2015. Online prepub date: March 24, 2015.
Address correspondence to Andrew Bubak, Department of Integrative Biology, University of Colorado-Denver, Campus Box 171, POB 173364, Denver, CO 80217-3364, USA. Tel: +1-605-481-0349; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 681-690, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687769
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Proof of Concept Studies Exploring the Safety and Functional Activity of Human Parthenogenetic-Derived Neural Stem Cells for the Treatment of Parkinson’s Disease

Rodolfo Gonzalez,* Ibon Garitaonandia,* Andrew Crain,† Maxim Poustovoitov,* Tatiana Abramihina,* Alexander Noskov,* Chuan Jiang,‡ Robert Morey,‡ Louise C. Laurent,‡ John D. Elsworth,§¶ Evan Y. Snyder,† D. Eugene Redmond, Jr.,§¶ and Ruslan Semechkin*

*International Stem Cell Corporation, Carlsbad, CA, USA
†Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
‡Department of Reproductive Medicine, UC San Diego, La Jolla, CA, USA
§Axion Research Foundation, Hamden, CT, USA
¶Departments of Psychiatry and Neurosurgery, Yale University School of Medicine, New Haven, CT, USA

Recent studies indicate that human pluripotent stem cell (PSC)-based therapies hold great promise in Parkinson’s disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying viable human embryos and can be used to generate an unlimited supply of neural stem cells for transplantation. Here we evaluate for the first time the safety and engraftment of human parthenogenetic stem cell-derived neural stem cells (hpNSCs) in two animal models: 6-hydroxydopamine (6-OHDA)-lesionedrodents and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates (NHPs). In both rodents and nonhuman primates, we observed successful engraftment and higher dopamine levels in hpNSC-transplanted animals compared to vehicle control animals, without any adverse events. These results indicate that hpNSCs are safe, well tolerated, and could potentially be a source for cell-based therapies in PD.

Key words: Parthenogenetic stem cells; Neural stem cells (NSCs); Parkinson’s disease (PD)

Received January 13, 2015; final acceptance March 9, 2015. Online prepub date: March 24, 2015.
Address correspondence to Dr. Ruslan Semechkin, International Stem Cell Corporation, 5950 Priestly Drive, Carlsbad, CA 92008, USA. E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 691-702, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X684600
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
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Human Neural Stem Cell Transplantation Provides Long-Term Restoration of Neuronal Plasticity in the Irradiated Hippocampus

Munjal M. Acharya,*1 Susanna Rosi,†‡1 Timothy Jopson,† and Charles L. Limoli*

*Department of Radiation Oncology, University of California, Irvine, CA, USA
†Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, CA, USA
‡Physical Therapy and Rehabilitation Science, University of California, San Francisco, CA, USA

For the majority of CNS malignancies, radiotherapy provides the best option for forestalling tumor growth, but is frequently associated with debilitating and progressive cognitive dysfunction. Despite the recognition of this serious side effect, satisfactory long-term solutions are not currently available and have prompted our efforts to explore the potential therapeutic efficacy of cranial stem cell transplants. We have demonstrated that intrahippocampal transplantation of human neural stem cells (hNSCs) can provide long-lasting cognitive benefits using an athymic rat model subjected to cranial irradiation. To explore the possible mechanisms underlying the capability of engrafted cells to ameliorate radiation-induced cognitive dysfunction we analyzed the expression patterns of the behaviorally induced activity-regulated cytoskeleton-associated protein (Arc) in the hippocampus at 1 and 8 months postgrafting. While immunohistochemical analyses revealed a small fraction (4.5%) of surviving hNSCs in the irradiated brain that did not express neuronal or astroglial makers, hNSC transplantation impacted the irradiated microenvironment of the host brain by promoting the expression of Arc at both time points. Arc is known to play key roles in the neuronal mechanisms underlying long-term synaptic plasticity and memory and provides a reliable marker for detecting neurons that are actively engaged in spatial and contextual information processing associated with memory consolidation. Cranial irradiation significantly reduced the number of pyramidal (CA1) and granule neurons (DG) expressing behaviorally induced Arc at 1 and 8 months postirradiation. Transplantation of hNSCs restored the expression of plasticity-related Arc in the host brain to control levels. These findings suggest that hNSC transplantation promotes the long-term recovery of host hippocampal neurons and indicates that one mechanism promoting the preservation of cognition after irradiation involves trophic support from engrafted cells.

Key words: Human neural stem cells (hNSCs); Transplantation; Radiation; Hippocampus; Activity-regulated cytoskeleton-associated protein (Arc)

Received March 19, 2014; final acceptance September 3, 2014. Online prepub date: October 6, 2014.
1These authors provided equal contribution to this work.
Address correspondence to Prof. Charles L. Limoli, Department of Radiation Oncology, University of California Irvine, Medical Sciences I, Room B-146B, Irvine, CA 92697-2695, USA. Tel: +1 (949) 824-3053; Fax: +1 (949) 824-3566; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 703-719, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X685140
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Exogenous Adult Postmortem Neural Precursors Attenuate Secondary Degeneration and Promote Myelin Sparing and Functional Recovery Following Experimental Spinal Cord Injury

Stephana Carelli,*1 Toniella Giallongo,*1 Giovanni Marfia,*1 Davide Merli,* Luisa Ottobrini,§ Anna Degrassi,‡ Michele D. Basso,† Anna Maria Di Giulio,* and Alfredo Gorio*

*Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy
†Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
‡Pharmacology Department, BU Oncology, Nerviano Medical Sciences, Milan, Italy
§Department of Medical-Surgical Pathophysiology and Transplant, University of Milan, Milan, Italy

Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neurological dysfunctions. Neural stem cells from the subventricular zone of the forebrain have been considered a potential tool for cell replacement therapies. We recently isolated a subclass of neural progenitors from the cadaver of mouse donors. These cells, named postmortem neural precursor cells (PM-NPCs), express both erythropoietin (EPO) and its receptor. Their EPO-dependent differentiation abilities produce a significantly higher percentage of neurons than regular NSCs. The cholinergic yield is also higher. The aim of the present study was to evaluate the potential repair properties of PM-NPCs in a mouse model of traumatic SCI. Labeled PM-NPCs were administered intravenously; then the functional recovery and the fate of transplanted cells were studied. Animals transplanted with PM-NPCs showed a remarkable improved recovery of hindlimb function that was evaluated up to 90 days after lesion. This was accompanied by reduced myelin loss, counteraction of the invasion of the lesion site by the inflammatory cells, and an attenuation of secondary degeneration. PM-NPCs migrate mostly at the injury site, where they survive at a significantly higher extent than classical NSCs. These cells accumulate at the edges of the lesion, where a reach neuropile is formed by MAP2- and β-tubulin III-positive transplanted cells that are also mostly labeled by anti-ChAT antibodies.

Key words: Spinal cord injury (SCI); Neural stem cells; Transplantation; Regenerative medicine; Animal behavior; Inflammation

Received May 14, 2014; final acceptance October 6, 2014. Online prepub date: October 8, 2014.
1These authors provided equal contribution to this work.

Address correspondence to Alfredo Gorio, Laboratory of Pharmacology, Department of Health Sciences University of Milan, Polo H. San Paolo, via A di Rudini 8, 20142 Milan, Italy. Tel: +390250323032; Fax: +390250323033; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 721-735, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X685311
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Human Umbilical Cord Blood Cells Induce Neuroprotective Change in Gene Expression Profile in Neurons After Ischemia Through Activation of AktPathway

M. D. Shahaduzzaman,*† Vijay Mehta,* Jason E. Golden,*‡ Derrick D. Rowe,‡ Suzanne Green,* Ramya Tadinada,* Elspeth A. Foran,* Paul R. Sanberg,*† Keith R. Pennypacker,*‡ and Alison E. Willing*†‡

*Center of Excellence for Aging and Brain Repair, University of South Florida, Tampa, FL, USA
†Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL, USA
‡Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA

Human umbilical cord blood (HUCB) cell therapies have shown promising results in reducing brain infarct volume and most importantly in improving neurobehavioral function in rat permanent middle cerebral artery occlusion, a model of stroke. In this study, we examined the gene expression profile in neurons subjected to oxygen-glucose deprivation (OGD) with or without HUCB treatment and identified signaling pathways (Akt/MAPK) important in eliciting HUCB-mediated neuroprotective responses. Gene chip microarray analysis was performed using RNA samples extracted from the neuronal cell cultures from four experimental groups: normoxia, normoxia + HUCB, OGD, and OGD + HUCB. Both quantitative RT-PCR and immunohistochemistry were carried out to verify the microarray results. Using the Genomatix software program, promoter regions of selected genes were compared to reveal common transcription factor-binding sites and, subsequently, signal transduction pathways. Under OGD condition, HUCB cells significantly reduced neuronal loss from 68% to 44% [one-way ANOVA, F(3, 16) = 11, p = 0.0003]. Microarray analysis identified mRNA expression of Prdx5, Vcam1, CCL20, Alcam, and Pax6 as being significantly altered by HUCB cell treatment. Inhibition of the Akt pathway significantly abolished the neuroprotective effect of HUCB cells [one-way ANOVA, F(3, 11) = 8.663, p = 0.0031]. Our observations show that HUCB neuroprotection is dependent on the activation of the Aktsignaling pathway that increases transcription of the Prdx5 gene. We concluded that HUCB cell therapy would be a promising treatment for stroke and other forms of brain injury by modifying acute gene expression to promote neural cell protection.

Key words: Ischemia; Human umbilical cord blood (HUCB); Gene expression; Cell signaling pathways

Received July 9, 2014; final acceptance October 30, 2014. Online prepub date: November 13, 2014.
Address correspondence to Alison E. Willing, Ph.D., Center of Excellence for Aging and Brain Repair, USF Morsani College of Medicine, 12901 Bruce B. Downs Blvd., MDC78, Tampa, FL 33612, USA. Tel: +1 813-974-7812; Fax: +1 813-974-3078; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 737-749, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X685429
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Translation of Cell Therapies to the Clinic: Characteristics of Cell Suspensions in Large-Diameter Injection Cannulae

Eduardo M. Torres,* Matthieu Trigano,† and Stephen B. Dunnett*

*Cardiff University, Biomedical Sciences, Cardiff, UK
†Université Pierre et Marie Curie, Paris, France

With the use of cell replacement therapies as a realistic prospect for conditions such as Parkinson’s and Huntington’s diseases, the logistics of the delivery of cell suspensions to deep brain targets is a topic for consideration. Because of the large cannulaerequired for such procedures, we need to consider the behavior of cell suspensions within the cannulae if we are to ensure that the injected cells are distributed as intended within the target tissue. We have investigated the behavior of primary embryonic cell suspensions of neural tissue, in cannulae of different diameters, using a protocol designed to mimic the handling and injection of cells during clinical application. Internal cannula diameter had a large effect on the distribution of cells during their dispensation from the syringe. In vertical or near vertical cannulae, cells settled toward the tip of the needle, and were dispensed unevenly, with the majority of cells emerging in the first 10–20% of the injectate. In horizontal or nearhorizontal cannulae, we observed the opposite effect, such that few cells were dispensed in the first 80% of the injectate, and the majority emerged in the final 10–20%. Use of a glass cannula showed that the results obtained using the horizontal cannula were caused by settling and adherence of the cells on the side of the cannulae, such that during dispensation, the overlying, cell-free solution was dispensed first, prior to the emergence of the cells. We show that the behavior of cells in such cannulae is affected by the cannula diameter, and by the material of the cannula itself. In horizontal cannulae, uneven expulsion of cells from the needle can be ameliorated by regular rotation of the cannula during the procedure. We discuss the potential impact of these observations on the translation of cell therapies to the clinic.

Key words: Cell transplantation; Cell suspensions; Implantation instrument; Surgical cannula; Settling; Sedimentation

Received August 1, 2014; final acceptance November 5, 2014. Online prepub date: November 13, 2014.
Address correspondence to E. M. Torres, Cardiff University, Biomedical Sciences Building, Museum Avenue, Cardiff CF10 3AX, UK. Tel: +44 (0) 2920 874115; Fax: +44 (0) 2920 876749; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it

Keywords and related topics:
Adipose stem cells; Losartan; Stem cell microenvironment; Muscular dystrophy; Skeletal muscle regeneration; Heatstroke; Human exfoliated deciduous teeth pulp stem cells; Brain; Thermoregulation;
 Neurologic severity scores
; Multiple organs
; Bone morphogenetic protein 9 (BMP9); Bone morphogenetic protein 13 (BMP13); C3H10T1/2 cells; 
Cardiomyocytes
Ion channel current; 
Mesenchymal stem cells
; Hair follicles; 
Gene therapy; 
Lentivirus;
Type 1 diabetes
; Chemical diabetes
; Islet remodeling; 
b-Cell regeneration; 
Insulin-producing cells; 
Bone marrow stem cells; Hematopoietic progenitors; Bone marrow transplantation; Mesenchymal stromal cells (MSCs); UCX®; Stem cell transplantation; Fibroblast and keratinocyte migration; BM-MSC mobilization; G-CSF; Skin regeneration; Pluripotent stem cells; Embryonic stem cells; Induced pluripotent stem cells; Immunogenicity; Major histocompatibility complex (MHC); Immune privilege; Embryonic stem cells; Neural induction (NI); Neural progenitor cells; Wnt; Intra-arterial (IA) delivery; Biodistribution; Bone marrow-derived mesenchymal cells (BM-MSCs);; Cerebral ischemia; Single-photon emission computed to- mography (SPECT) imaging; Xenografting