Cell Medicine 9(3) Abstracts

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Cell Medicine, Vol. 9, pp. 67-71, 2017
2155-1790/17 $90.00 + .00
DOI: https://doi.org/10.3727/215517917X
693393
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Commentary

Regenerative Rehabilitation: An Innovative and Multifactorial Approach to Recovery From Stroke and Brain Injury

Samantha M. Portis and Paul R. Sanberg

Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

There is currently a dearth of treatment options for stroke or traumatic brain injury that can restore cognitive and motor function. Regenerative and translational medicine have ushered forth promising new methods for mediating recovery in the central nervous system, the most salient of which are rehabilitation and stem cell therapies that, when combined, result in more pronounced recovery than one approach alone.

Key words: Regenerative rehabilitation; Stem cells; Physical therapy; Stroke; Traumatic brain injury; Regeneration

Received September 14, 2016; final acceptance March 20, 2017. Online prepub date: April 14, 2017.
Address correspondence to Paul R. Sanberg, Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC 78, Tampa, FL 33612, USA. Tel: (813)974-3154; Fax: (813)974-3078; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Medicine, Vol. 9, pp. 73-85, 2017
2155-1790/17 $90.00 + .00
DOI: https://doi.org/10.3727/215517916X693384
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Neurovascular Cell Sheet Transplantation in a Canine Model of Intracranial Hemorrhage

Woo-Jin Lee,*†1 Jong Young Lee,‡1 Keun-Hwa Jung,*† Soon-Tae Lee,*† Hyo Yeol Kim,§ Dong-Kyu Park,† Jung-Suk Yu,† So-Yun Kim,† Daejong Jeon,† Manho Kim,†‡ Sang Kun Lee,*† Jae-Kyu Roh,*†¶ and Kon Chu*†

*Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, South Korea
†Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
‡Department of Neurosurgery, Kangdong Sacred Heart Hospital, Seoul, South Korea
§Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
¶Department of Neurology, The Armed Forces Capital Hospital, Gyeunggido, South Korea

Cell-based therapy for intracerebral hemorrhage (ICH) has a great therapeutic potential. However, methods to effectively induce direct regeneration of the damaged neural tissue after cell transplantation have not been established, which, if done, would improve the efficacy of cell-based therapy. In this study, we aimed to develop a cell sheet with neurovasculogenic potential and evaluate its usefulness in a canine ICH model. We designed a composite cell sheet made of neural progenitors derived from human olfactory neuroepithelium and vascular progenitors from human adipose tissue-derived stromal cells. We also generated a physiologic canine ICH model by manually injecting and then infusing autologous blood under arterial pressure. We transplanted the sheet cells (cell sheet group) or saline (control group) at the cortex over the hematoma at subacute stages (2 weeks from ICH induction). At 4 weeks from the cell transplantation, cell survival, migration, and differentiation were evaluated. Hemispheric atrophy and neurobehavioral recovery were also compared between the groups. As a result, the cell sheet was rich in extracellular matrices and expressed neurotrophic factors as well as the markers for neuronal development. After transplantation, the cells successfully survived for 4 weeks, and a large portion of those migrated to the perihematomal site and differentiated into neurons and pericytes (20% and 30% of migrated stem cells, respectively). Transplantation of cell sheets alleviated hemorrhage-related hemispheric atrophy p = 0.042) and showed tendency for improving functional recovery ( p = 0.062). Therefore, we concluded that the cell sheet transplantation technique might induce direct regeneration of neural tissue and might improve outcomes of intracerebral hemorrhage.

Key words: Cell sheet; Cell therapy; Intracerebral hemorrhage (ICH); Neurovascular progenitor; Transplantation

Received September 27, 2016; final acceptance December 15, 2016. Online prepub date: December 21, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Keun-Hwa Jung, M.D., Ph.D., Department of Neurology, Seoul National University Hospital, 101 Daehak-roJongno-gu, Seoul 110-744, South Korea. Tel: +82-2-20724901; Fax: +82-2-36724949; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Kon Chu, M.D., Ph.D., Department of Neurology, Seoul National University Hospital, 101 Daehak-roJongno-gu, Seoul 110-744, South Korea. Tel: +82-2-2072-1878; Fax: + 82-2-2072-7424; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Medicine, Vol. 9, pp. 87-102, 2017
2155-1790/17 $90.00 + .00
DOI: https://doi.org/10.3727/215517916X693069
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

A Prospective, Nonrandomized, no Placebo-Controlled, Phase I/II Clinical Trial Assessing the Safety and Efficacy of Intramuscular Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells in Patients With Severe Buerger’s Disease

Jeong Chan Ra,*1 Euicheol C. Jeong,†‡1 Sung Keun Kang,* Seog Ju Lee,* and Kyoung Ho Choi*

*Biostar Stem Cell Research Institute, R Bio Co. Ltd., Seoul, Republic of Korea
†Department of Plastic Surgery, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
‡Department of Plastic and Reconstructive Surgery, College of Medicine, Seoul National University, Seoul, Republic of Korea

Buerger’s disease is a rare and severe disease affecting the blood vessels of the limbs. Adipose tissue-derived mesenchymal stem cells (ADSCs) have the potential to cure Buerger’s disease when developed as a stem cell drug. In the present study, we conducted a prospective, nonrandomized, no placebo-controlled, phase I/II clinical trial with a 2-year follow-up questionnaire survey. A total of 17 patients were intramuscularly administered autologous ADSCs at a dose of 5 million cells/kg. The incidence of adverse events (AEs), adverse drug reaction (ADR), and serious adverse events (SAEs) was monitored. No ADRs and SAEs related to stem cell treatment occurred during the 6-month follow-up. In terms of efficacy, the primary endpoint was increase in total walking distance (TWD). The secondary endpoint was improvement in rest pain, increase in pain-free walking distance (PFWD), toe–brachial pressure index (TBPI), transcutaneous oxygen pressure (TcPO2), and arterial brachial pressure index (ABPI). ADSCs demonstrated significant functional improvement results including increased TWD, PFWD, and rest pain reduction. No amputations were reported during the 6-month clinical trial period and in the follow-up questionnaire survey more than 2 years after the ADSC injection. In conclusion, intramuscular injection of ADSCs is very safe and is shown to prompt functional improvement in patients with severe Buerger’s disease at a dosage of 300 million cells per 60 kg of body weight. However, the confirmatory therapeutic efficacy and angiogenesis need further study.

Key words: Buerger’s disease; Mesenchymal stem cells (MSCs); Adipose tissue; Autologous

Received May 10, 2016; final acceptance October 28, 2016. Online prepub date: October 3, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Jeong Chan Ra, D.V.M., Ph.D., Biostar Stem Cell Research, Institute, R Bio Co. Ltd., 2-305 IT Castle, Gasan-dong, Geumcheon-gu, Seoul 08506, Republic of Korea. Tel: +82-2-874-0686; Fax: +82-2-874-2356; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Medicine, Vol. 9, pp. 103-116, 2017
2155-1790/17 $90.00 + .00
DOI: https://doi.org/10.3727/215517917X693401
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Human Adipose-Derived Mesenchymal Stem Cells Respond to Short-Term Hypoxia by Secreting Factors Beneficial for Human Islets In Vitro and Potentiate Antidiabetic Effect In Vivo

Simen W. Schive,*†‡ Mohammad Reza Mirlashari,§¶ Grete Hasvold,# Mengyu Wang,§ Dag Josefsen,§ Hans Petter Gullestad,** Olle Korsgren,†† Aksel Foss,*†‡ Gunnar Kvalheim,§ and Hanne Scholz*†‡

*Department of Transplant Medicine, Oslo University Hospital, Oslo, Norway
†Institute for Surgical Research, Oslo University Hospital, Oslo, Norway
‡Institute of Clinical Medicine, University of Oslo, Oslo, Norway
§Section for Cell Therapy, Oslo University Hospital, Oslo, Norway
¶Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway
#Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
**Department of Surgery, Oslo University Hospital, Oslo, Norway
††Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

Adipose-derived mesenchymal stem cells (ASCs) release factors beneficial for islets in vitro and protect against hyperglycemia in rodent models of diabetes. Oxygen tension has been shown to induce metabolic changes and alter ASCs’ release of soluble factors. The effects of hypoxia on the antidiabetic properties of ASCs have not been explored. To investigate this, we incubated human ASCs for 48 h in 21% (normoxia) or 1% O2
(hypoxia) and compared viability, cell growth, surface markers, differentiation capability, and soluble factors in the conditioned media (CM). Human islets were exposed to CM from ASCs incubated in either normoxia or hypoxia, and islet function and apoptosis after culture with or without proinflammatory cytokines were measured. To test hypoxic preconditioned ASCs’ islet protective effects in vivo, ASCs were incubated for 48 h in normoxia or hypoxia before being injected into Balb/c Rag 1−/− immunodeficient mice with streptozotocin-induced insulitis. Progression of diabetes and insulin content of pancreas were measured. We found that incubation in hypoxia was well tolerated by ASCs and that levels of VEGF-A, FGF-2, and bNGF were elevated in CM from ASCs incubated in hypoxia compared to normoxia, while levels of HGF, IL-8, and CXCL1 were reduced. CM from ASCs incubated in hypoxia significantly improved human islet function and reduced apoptosis after culture, and reduced cytokine-induced apoptosis. In our mouse model, pancreas insulin content was higher in both groups receiving ASCs compared to control, but the mice receiving preconditioned ASCs had lower random and fasting blood glucose, as well as improved oral glucose tolerance compared to untreated mice. In conclusion, our in vitro results indicate that the islet protective potential of ASCs improves in hypoxia, and we give insight into factors involved in this. Finally we show that hypoxic preconditioning potentiates ASCs’ antidiabetic effect in vivo.

Key words: Adipose-derived stem cells (ASCs); Hypoxia; Islet transplantation; Diabetes

Received November 4, 2016; final acceptance March 24, 2017. Online prepub date: April 14, 2017.
Address correspondence to Simen W. Schive, M.D., Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, P.O. Box 4950 NydalenN-0424 Oslo, Norway. Tel: +47-23073520; Fax: 47-23073630; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Medicine, Vol. 9, pp. 117-125, 2017
2155-1790/17 $90.00 + .00
DOI: https://doi.org/10.3727/215517916X693375
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Higher Serum Alanine Transaminase Levels in Male Urokinase-Type Plasminogen Activator-Transgenic Mice Are Associated With Improved Engraftment of Hepatocytes but not Liver Sinusoidal Endothelial Cells

Marina E. Fomin,* Ashley I. Beyer,* Jean Publicover,† Kai Lu,* Sonia Bakkour,* Graham Simmons,*‡ and Marcus O. Muench*‡

*Blood Systems Research Institute, San Francisco, CA, USA
†Department of Medicine, University of California, San Francisco, CA, USA
‡Department of Laboratory Medicine, University of California, San Francisco, CA, USA

The effects of sex on the degree of liver damage and human cell engraftment were investigated in immunodeficient urokinase-type plasminogen activator-transgenic (uPA-NOG) mice. Liver damage, measured by serum alanine transaminase (ALT) levels, was compared in male and female uPA-NOG mice of different ages. Male mice had significantly higher ALT levels than females with a median of 334 versus 158 U/L in transgenic homozygous mice, respectively. Mice were transplanted with human adult hepatocytes or fetal liver cells and analyzed for any correlation of engraftment of hepatocytes, liver sinusoidal endothelial cells (LSECs), and hematopoietic cells with the degree of liver damage. Hepatocyte engraftment was measured by human albumin levels in the mouse serum. Higher ALT levels correlated with higher hepatocyte engraftment, resulting in albumin levels in male mice that were 9.6 times higher than in females. LSEC and hematopoietic cell engraftment were measured by flow cytometric analysis of the mouse liver and bone marrow. LSEC and hematopoietic engraftment did not differ between male and female transplant recipients. Thus, the sex of uPANOG mice affects the degree of liver damage, which is reflected in the levels of human hepatocyte engraftment. However, the high levels of LSEC engraftment observed in uPA-NOG mice are not further improved among male mice, suggesting that a lower threshold of liver damage is sufficient to enhance endothelial cell engraftment. Previously described sex differences in human hematopoietic stem cell engraftment in immunodeficient mice were not observed in this model.

Key words: Alanine transaminase (ALT); Endothelial cells; Hepatocytes; Liver; Mice; Transgenic; Urokinase-type plasminogen activator

Received January 27, 2016; final acceptance November 18, 2016. Online prepub date: November 23, 2016.
Address correspondence to Marcus O. Muench, Ph.D., Blood Systems Research Institute, 270 Masonic Avenue, San Francisco, CA 94118, USA. Tel: (415) 901-0747; Fax: (415) 567-5899; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it