Cell Transplantation 23(2) Abstracts

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Cell Transplantation, Vol. 23, pp. 139-151, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X659916
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Birth and Death of Human β-Cells in Pancreases From Cadaver Donors, Autopsies, Surgical Specimens, and Islets Transplanted Into Mice

Francisco Caballero,* Karolina Siniakowicz,* Jennifer-Hollister-Lock,* Luisa Duran,* Hitoshi Katsuta,* Takatsugu Yamada,* Ji Lei,† Shaoping Deng,† Gunilla T. Westermark,‡ James Markmann,† Susan Bonner-Weir,* and Gordon C. Weir*

*Section on Islet Cell and Regenerative Biology, Research Division, Joslin Diabetes Center, Boston, MA, USA
†Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
‡Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

There is great interest in the potential of the human endocrine pancreas for regeneration by b-cell replication or neogenesis. Our aim was to explore this potential in adult human pancreases and in both islet and exocrine tissue transplanted into mice. The design was to examine pancreases obtained from cadaver donors, autopsies, and fresh surgical specimens and compare these findings with those obtained from islet and duct tissue grafted into the kidney. Islets and exocrine tissue were transplanted into normoglycemic ICR-SCID mice and studied 4 and 14 weeks later. β-Cell replication, as assessed by double staining for insulin and Ki67, was 0.22 ± 0.03% at 4 weeks and 0.13 ± 0.03% at 14 weeks. In contrast, no evidence of β-cell replication could be found in 11 cadaver donor and 10 autopsy pancreases. However, Ki67 staining of β-cells in frozen sections obtained at surgery was comparable to that found in transplanted islets. Evidence for neogenesis in transplanted pancreatic exocrine tissue was supported by finding β-cells within the duct epithelium and the presence of cells double stained for insulin and cytokeratin 19 (CK19). However, β-cells within the ducts never constituted more than 1% of the CK19-positive cells. With confocal microscopy, 7 of 12 examined cells expressed both markers, consistent with a neogeneic process. Mice with grafts containing islet or exocrine tissue were treated with various combinations of exendin-4, gastrin, and epidermal growth factor; none increased β-cell replication or stimulated neogenesis. In summary, human b-cells replicate at a low level in islets transplanted into mice and in surgical pancreatic frozen sections, but rarely in cadaver donor or autopsy pancreases. The absence of β-cell replication in many adult cadaver or autopsy pancreases could, in part, be an artifact of the postmortem state. Thus, it appears that adult human β-cells maintain a low level of turnover through replication and neogenesis.

Key words: Diabetes; Turnover; β-Cell neogenesis; β-Cell replication

Received December 9, 2011; final acceptance November 29, 2012. Online prepub date: January 2, 2013.
Address correspondence to Gordon C. Weir, M.D., Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA. Tel: +1-617-309-2581; Fax: +1-617-309-2650; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 153-165, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X658980
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Elevation of High-Mobility Group Box 1 After Clinical Autologous Islet Transplantation and Its Inverse Correlation With Outcomes

Takeshi Itoh,* Shuichi Iwahashi,* Mazhar A. Kanak,† Masayuki Shimoda,* Morihito Takita,* Daisuke Chujo,‡ Yoshiko Tamura,§ Ana M. Rahman,§ Wen Y. Chung,¶ Nicholas Onaca,§ P. Toby H. Coates,# Ashley R. Dennison,¶ Bashoo Naziruddin,§ Marlon F. Levy,§ and Shinichi Matsumoto*

*Baylor Research Institute, Dallas, TX, USA
†Institute of Biomedical Studies, Baylor University, Waco, TX, USA
‡Baylor Institute for Immunology Research, Dallas, TX, USA
§Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center at Dallas, Dallas, TX, USA
¶Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester NHS Trust, Leicester, UK
#Australian Islet Consortium, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, AUS

A major problem after clinical autologous islet transplantation (AIT) is the difficulty in achieving insulin independence. To follow up on our demonstration in a murine model that high-mobility group box 1 (HMGB1) was released from islets and involved in early loss of transplanted islets, we tested the role of HMGB1 in clinical AIT. Serum HMGB1 levels from 15 AIT patients were significantly elevated during islet infusion (7.6 ± 1.2 ng/ml) and 24 h after infusion (8.0 ± 1.4 ng/ml) compared to admission levels (2.4 ± 0.6 ng/ml). The first elevation of HMGB1 was associated with islet damage, but the later elevation was not. The change in the HMGB1 level from admission to first peak (DHMGB1) was significantly higher in the AIT group (8.1 ± 1.1 ng/ml) than in the pancreatectomy-only control (2.2 ± 0.5 ng/ml) (p < 0.05). Circulating serum levels of soluble receptor for advanced glycation end products (sRAGE) were also elevated during islet infusion. In vitro studies demonstrated that damaged human islets released HMGB1 but not sRAGE. In terms of outcomes, the insulin-free group showed significantly lower DHMGB1 (5.2 ± 0.6 ng/ml) and higher DsRAGE (2.3 ± 0.6 ng/ml) than the insulin-dependent group (10.6 ± 1.9 ng/ml and 0.7 ± 0.2 ng/ml, respectively). The DHMGB1 correlated with the number of white blood cell, IP-10, EGF, and eotaxin. In conclusion, serum HMGB1 was elevated in AIT and could be associated with inflammatory reactions that deteriorate islet engraftment. Therefore, anti-HMGB1 therapy might be a candidate for further improving the outcomes of clinical AIT.

Key words: Autologous islet transplantation (AIT); Islets; High-mobility group box 1 (HMGB1); Chronic pancreatitis; Pancreatectomy

Received February 15, 2012; final acceptance November 12, 2012. Online prepub date: December 4, 2012.
Address correspondence to Marlon F. Levy, M.D., Annette C. and Harold C. Simmons Transplant Institute, Baylor All Saints Medical Center, 1400 8th Ave, Fort Worth, TX 76104, USA. Tel: 817-922-4650; Fax: 817-922-4655; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 176-179, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X658007
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Autologous G-CSF-Mobilized Peripheral Blood CD34+ Cell Therapy for Diabetic Patients With Chronic Nonhealing Ulcer

Rica Tanaka,*† Haruchika Masuda,† Shunichi Kato,† Kotaro Imagawa,‡ Kazuo Kanabuchi,§ Chie Nakashioya,¶ Fumiaki Yoshiba,¶ Tsuyoshi Fukui,‡ Rie Ito,† Michiru Kobori,† Mika Wada,† Takayuki Asahara,† and Muneo Miyasaka‡

*Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan
†Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
‡Department of Plastic and Reconstructive Surgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan
§Department of Cardiovascular Surgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan
¶Department of Blood Transfusion Service, Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

Recently, animal studies have demonstrated the efficacy of endothelial progenitor cell (EPC) therapy for diabetic wound healing. Based on these preclinical studies, we performed a prospective clinical trial phase I/IIa study of autologous G-CSF-mobilized peripheral blood (PB) CD34+ cell transplantation for nonhealing diabetic foot patients. Diabetic patients with nonhealing foot ulcers were treated with 2 × 107 cells of G-CSF-mobilized PB CD34+ cells as EPC-enriched population. Safety and efficacy (wound closure and vascular perfusion) were evaluated 12 weeks posttherapy and further followed for complete wound closure and recurrence. A total of five patients were enrolled. Although minor amputation and recurrence were seen in three out of five patients, no death, other serious adverse events, or major amputation was seen following transplantation. Complete wound closure was observed at an average of 18 weeks with increased vascular perfusion in all patients. The outcomes of this prospective clinical study indicate the safety and feasibility of CD34+ cell therapy in patients with diabetic nonhealing wounds.

Key words: Nonhealing diabetic wound; Endothelial progenitor cells (EPC); Autologous cell therapy; Vasculogenesis; Wound healing

Received March 22, 2012; final acceptance October 9, 2012. Online prepub date: October 25, 2012.
Address correspondence to Rica Tanaka, M.D., Ph.D., Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan. Tel: +81-03-8313-3111; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 181-194, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X662426
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Scaffold-Free Cell Pellet Transplantations Can Be Applied to Periodontal Regeneration

Weihua Guo,*†‡1 Yong He,*§1 Xuepeng Tang,*§1 Gang Chen,‡ Haigang Shi,*† Kun Gong,*† Jing Zhou,*§ Lingying Wen,§ and Yan Jin*†

*Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi’an, China
†Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi’an, China
‡State Key Laboratory of Oral Disease, Sichuan University, Chengdu, China
§Department of Pedodontics, School of Stomatology, Fourth Military Medical University, Xi’an, China

Cell transplantation has emerged as a novel therapeutic strategy for periodontitis, and the adoption of cell pellet offers advantages by secreting abundant extracellular matrix (ECM) and eliminating the adverse effect of cell carriers. This study aimed to fabricate scaffold-free periodontal ligament stem cell (PDLSC) pellets (MUCPs) and to evaluate their regeneration potential. We constructed monolayer cell pellets (MCPs) by fabricating and culturing multilayered cell sheets (MUCS) and constructed MUCPs from the MUCS. Immunochemistry, scanning electron microscope, real-time PCR, and Western blot analysis showed higher levels of COL-I, COLIII, fibronectin, and laminin in the MUCPs. Furthermore, the massive increase in ECM secretion improved cell adhesion, migration, and proliferation. Finally, upon transplantation into the omentum sac and periodontal defects, all the transplants formed regular aligned cementum/PDL-like complex, but the mineral deposit and fiber alignment were more obvious in the MUCPs than in the MCPs. Altogether, our results suggest that MUCPs may be a promising alternative to periodontal repair for future clinical application.

Key words: Periodontal ligament stem cells (PDLSCs); Cell pellet; Extracellular matrix (ECM); Microenvironment; Periodontal regeneration

Received March 30, 2011; final acceptance October 14, 2012. Online prepub date: January 28, 2013.
1These authors provided equal contribution to this work.
Address correspondence to Prof. Yan Jin, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, 145 West Changle Road, Xi’an 710032, China. Tel: +86 29 84776472; Fax: +86 29 83218039; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Prof. Lingying Wen, Ph.D., Department of Pedodontics, School of Stomatology, Fourth Military Medical University, 145 West Changle Road, Xi’an 710032, China. Tel: +86 29 8477 4010; Fax: +86 29 83218039. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 195-206, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X659871
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Comparison of Human Adipose-Derived Stem Cells and Bone Marrow-Derived Stem Cells in a Myocardial Infarction Model

Jeppe Grøndahl Rasmussen,*† Ole Frøbert,‡ Claus Holst-Hansen,§ Jens Kastrup,¶ Ulrik Baandrup,#** Vladimir Zachar,† Trine Fink,† and Ulf Simonsen*

*Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark
†Laboratory for Stem Cell Research, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
‡Department of Cardiology, Örebro University Hospital, Örebro, Sweden
§Department of Cardiology, Head and Heart Centre, Aalborg Hospital, Århus University Hospital, Aalborg, Denmark
¶Cardiac Stem Cell Laboratory, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
#Department of Pathology, Vendsyssel Hospital, Hjørring, Denmark
**Center for Clinical Research, Aalborg University, Aalborg, Denmark

Treatment of myocardial infarction (MI) with bone marrow-derived mesenchymal stem cells and recently also adipose-derived stem cells has shown promising results. In contrast to clinical trials and their use of autologous bone marrow-derived cells from the ischemic patient, the animal MI models are often using young donors and young, often immune-compromised, recipient animals. Our objective was to compare bone marrow-derived mesenchymal stem cells with adipose-derived stem cells from an elderly ischemic patient in the treatment of MI using a fully grown non-immune-compromised rat model. Mesenchymal stem cells were isolated from adipose tissue and bone marrow and compared with respect to surface markers and proliferative capability. To compare the regenerative potential of the two stem cell populations, male Sprague–Dawley rats were randomized to receive intramyocardial injections of adipose-derived stem cells, bone marrow-derived mesenchymal stem cells, or phosphate-buffered saline 1 week following induction of MI. After 4 weeks, left ventricular ejection fraction (LVEF) was improved in the adipose-derived stem cell group, and scar wall thickness was greater compared with the saline group. Adipose-derived as well as bone marrow-derived mesenchymal stem cells prevented left ventricular end diastolic dilation. Neither of the cell groups displayed increased angiogenesis in the myocardium compared with the saline group. Adipose-derived stem cells from a human ischemic patient preserved cardiac function following MI, whereas this could not be demonstrated for bone marrow-derived mesenchymal stem cells, with only adipose-derived stem cells leading to an improvement in LVEF. Neither of the stem cell types induced myocardial angiogenesis, raising the question whether donor age and health have an effect on the efficacy of stem cells used in the treatment of MI.

Key words: Myocardial infarction; Cell therapy; Left ventricular function; Remodeling; Angiogenesis

Received May 30, 2012; final acceptance November 16, 2012. Online prepub date: December 4, 2012.
Address correspondence to Trine Fink, Laboratory for Stem Cell Research, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 3B, 9220 Aalborg, Denmark. Tel: +45-9940-7550; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 207-220, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X659862
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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The Impact of Stem Cells on Electron Fluxes, Proton Translocation, and ATP Synthesis in Kidney Mitochondria After Ischemia/Reperfusion

Hellen J. V. Beiral,*† Clara Rodrigues-Ferreira,*†‡ Aline M. Fernandes,*† Sabrina R. Gonsalez,†§ Nicoli C. Mortari,* Christina M. Takiya,* Martha M. Sorenson,†‡ Cícero Figueiredo-Freitas,†‡ Antonio Galina,‡¶ and Adalberto Vieyra*†

*Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
†National Institute of Science and Technology for Structural Biology and Bioimaging, Rio de Janeiro, Brazil
‡Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
§Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
¶National Institute of Science and Technology in Exocitotoxicity and Neuroprotection, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Tissue damage by ischemia/reperfusion (I/R) results from a temporary cessation of blood flow followed by the restoration of circulation. The injury depresses mitochondrial respiration, increases the production of reactive oxygen species (ROS), decreases the mitochondrial transmembrane potential, and stimulates invasion by inflammatory cells. The primary objective of this work was to address the potential use of bone marrow stem cells (BMSCs) to preserve and restore mitochondrial function in the kidney after I/R. Mitochondria from renal proximal tubule cells were isolated by differential centrifugation from rat kidneys subjected to I/R (clamping of renal arteries followed by release of circulation after 30 min), without or with subcapsular administration of BMSCs. Respiration starting from mitochondrial complex II was strongly affected following I/R. However, when BMSCs were injected before ischemia or together with reperfusion, normal electron fluxes, electrochemical gradient for protons, and ATP synthesis were almost completely preserved, and mitochondrial ROS formation occurred at a low rate. In homogenates from cultured renal cells transiently treated with antimycin A, the coculture with BMSCs induced a remarkable increase in protein S-nitrosylation that was similar to that found in mitochondria isolated from I/R rats, evidence that BMSCs protected against both superoxide anion and peroxynitrite. Labeled BMSCs migrated to damaged tubules, suggesting that the injury functions as a signal to attract and host the injected BMSCs. Structural correlates of BMSC injection in kidney tissue included stimulus of tubule cell proliferation, inhibition of apoptosis, and decreased inflammatory response. Histopathological analysis demonstrated a score of complete preservation of tubular structures by BMSCs, associated with normal plasma creatinine and urinary osmolality. These key findings shed light on the mechanisms that explain, at the mitochondrial level, how stem cells prevent damage by I/R. The action of BMSCs on mitochondrial functions raises the possibility that autologous BMSCs may help prevent I/R injuries associated with transplantation and acute renal diseases.

Key words: Kidney mitochondria; Bone marrow stem cells (BMSCs); Ischemia/reperfusion (IR); Mitochondrial respiration; ATP synthesis

Received May 9, 2012; final acceptance November 19, 2012. Online prepub date: December 4, 2012.
Address correspondence to Adalberto Vieyra, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Building G Health Sciences Center, Rio de Janeiro 21941-590, Brazil. Tel: +55 21 25626520; Fax: +55 21 22808193; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 221-238, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X661355
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Notch Signaling-Mediated Neural Lineage Selection Facilitates Intrastriatal Transplantation Therapy for Ischemic Stroke by Promoting Endogenous Regeneration in the Hippocampus

Tao Yang,*† Ling-yun Liu,‡ Yuan-yuan Ma,§ and Wei Zhang†

*Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, P. R. China
†Department of Pharmacology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, P. R. China
‡Department of Neurology, Shanghai Yangpu District Central Hospital, Shanghai, P. R. China
§State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, P. R. China

Acquisition of highly efficient neural differentiation based on understanding of initial lineage commitment of human embryonic stem (hES) cells remains a challenge. This study describes a simple three-stage protocol to induce hES cells into neural lineage cells using a 2-week coculture with murine bone marrow stromal cell (BMSC) PA6 followed by a 2-week propagation culture in PA6-conditioned medium and an additional 2-week selection culture in chemically defined neurobasal medium. This protocol generated a relatively high yield of neural lineage cells without mesodermal and endodermal lineage cell contamination. Notably, we demonstrated that PA6 coculture can significantly enhance the expression level of Notch signaling components and promote neural lineage entry of hES cell derivatives. Manipulation of Notch signaling can boost or suppress neural differentiation of hES cell derivatives, suggesting that Notch signaling may underlie the PA6-mediated neural induction. In vivo studies demonstrated that derived neural cells could improve the cognitive function of ischemic stroke rats. Intrastriatal human neural cell grafts were noted to migrate to damaged cerebral regions, enhance basic fibroblast growth factor production in the hippocampus, and restore the pyramidal neuron density and morphology in the hippocampal CA1 region, although only a small number of human donor cells were present in the hippocampus, suggesting that donor cells can boost hippocampal reconstruction by promoting the endogenous regeneration process. These findings demonstrate a pivotal role for Notch in hES cell fate determination and that manipulation of Notch signaling is therefore likely to be a key factor in taking command of hES cell lineage choice. This study suggested the potential of utilizing PA6 coculture to imitate the embryonic niche for hES cell neural induction via Notch signaling and a high application potential of BMSC-involved protocol, which can yield a whole lineage of human neural cells to promote endogenous regeneration in the hippocampus upon transplantation for potential therapy of ischemic stroke.

Key words: Embryonic stem cell; Neural differentiation; Transplantation; Stroke; Notch

Received June 5, 2011; final acceptance December 6, 2012. Online prepub date: January 2, 2013.
Address correspondence to Prof. Wei Zhang, Department of Pharmacology, School of Basic Medicine, Hebei Medical University, 326 South Xinshi Road, Shijiazhuang 050091, P. R. China. Tel: +86-311-86265319; Fax: +86-311-85933288; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Dr. Tao Yang, Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, P.R. China. Tel: +86-21-61569714; Fax: +86-21-33923060; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 239-252, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X669752
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Primary Bone Marrow Mesenchymal Stromal Cells Rescue the Axonal Phenotype of Twitcher Mice

Catarina Oliveira Miranda,*† Carla Andreia Teixeira,* Vera Filipe Sousa,*† Telma Emanuela Santos,* Márcia Almeida Liz,* Ana Maio Marques,* Perpétua Pinto-do-Ó,‡ and Mónica Mendes Sousa*

*Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal
†ICBAS, Universidade do Porto, Porto, Portugal
‡Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal

Krabbe’s disease (KD) is a demyelinating disorder caused by the deficiency of lysosomal galactocerebrosidase (GALC), affecting both the central (CNS) and the peripheral nervous system (PNS). A current therapy, hematopoietic stem cell transplantation (HSCT), is ineffective at correcting the PNS pathology. We have previously shown that systemic delivery of immortalized bone marrow-derived murine mesenchymal stromal cells (BM-MSCs) diminishes the neuropathology of transplanted Twitcher mice, a murine model of KD. In this study, to move one step closer to clinical application, the effectiveness of a systematic delivery of primary BM-MSCs to promote recovery of the Twitcher PNS was assessed. Primary BM-MSCs grafted to the Twitcher sciatic nerve led to increased GALC activity that was not correlated to decreased psychosine (the toxic GALC substrate) accumulation. Nevertheless, BM-MSC transplantation rescued the axonal phenotype of Twitcher mice in the sciatic nerve, with an increased density of both myelinated and unmyelinated axons in transplanted animals. Whereas no increase in myelination was observed, upon transplantation an increased proliferation of Schwann cell precursors occurred. Supporting these findings, in vitro, BM-MSCs promoted neurite outgrowth of Twitcher sensory neurons and proliferation of Twitcher Schwann cells. Moreover, BM-MSCs expressed nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and promoted increased BDNF synthesis by neighboring Schwann cells. Besides their action in neurons and glia, BM-MSCs led to macrophage activation in Twitcher sciatic nerves. In summary, primary BM-MSCs diminish the neuropathology of Twitcher sciatic nerves by coordinately affecting neurons, glia, and macrophages.

Key words: Krabbe’s disease (KD); Twitcher mice; Axonal degeneration; Bone marrow-derived mesenchymal stromal cells (BM-MSCs)

Received October 25, 2011; final acceptance June 15, 2012. Online prepub date: June 27, 2013.
Address correspondence to Mónica M. Sousa, Nerve Regeneration Group, IBMC, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal. Tel: +351226074900; Fax +351226099157; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 253-262, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X661328
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Survival of Neural Progenitors Allografted Into the CNS of Immunocompetent Recipients Is Highly Dependent on Transplantation Site

M. Janowski,*†‡§ C. Engels,*† M. Gorelik,*† A. Lyczek,*† S. bernard,*† J. W. M. Bulte,*†¶#** and P. Walczak*†,††

*Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
†Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
‡NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
§Department of Neurosurgery, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
¶Department of Chemical and Biomolecular Engineering, The Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA
#Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
**Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
††Department of Radiology, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland

Allografts continue to be used in clinical neurotransplantation studies; hence, it is crucial to understand the mechanisms that govern allograft tolerance. We investigated the impact of transplantation site within the brain on graft survival. Mouse [Friend leukemia virus, strain B (FVB)] glial precursors, transfected with luciferase, were injected (3 × 105) into the forceps minor (FM) or striatum (STR). Immunodeficient rag2-/- and immunocompetent BALB/c mice were used as recipients. Magnetic resonance imaging (MRI) confirmed that cells were precisely deposited at the selected coordinates. The graft viability was assessed noninvasively with bioluminescent imaging (BLI) for a period of 16 days. Regardless of implantation site, all grafts (n = 10) deposited in immunodeficient animals revealed excellent survival. In contrast, immunocompetent animals only accepted grafts at the STR site (n = 10), whereas all the FM grafts were rejected (n = 10). To investigate the factors that led to rejection of FM grafts, with acceptance of STR grafts, another group of animals (n = 19) was sacrificed during the prerejection period, on day 5. Near-infrared fluorescence imaging with IRDye 800CW–polyethylene glycol probe displayed similar blood–brain barrier disruption at both graft locations. The morphological distribution of FM grafts was cylindrical, parallel to the needle track, whereas cells transplanted into the STR accumulated along the border between the STR and the corpus callosum. There was significantly less infiltration by both innate and adaptive immune cells in the STR grafts, especially along the calloso-striatal border. With allograft survival being dependent on the transplantation site, the anatomical coordinates of the graft target should always be taken into account as it may determine the success or failure of therapy.

Key words: Transplantation; Brain; Rejection; Stem cells; Glial progenitors

Received April 24, 2012; final acceptance December 3, 2012. Online prepub date: January 2, 2013.
Address correspondence to Piotr Walczak, M.D., Associate Professor, The Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Broadway Research Building, Room 649, 733 N Broadway, Baltimore, MD 21205, USA. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it