Current research and clinical trials*

4. David Harris and Ian Rogers. (2008) Umbilical Cord Blood: a unique source of pluripotent stem cells for regenerative medicine. Current Stem Cell Research and Therapy 2(4):301-9
5. Hutson EL, Boyer S, Genever PG. (2005) Rapid isolation, expansion and differentiation of osteoprogenitors from full-term cord blood. Tissue Engineering 11(9-10):1407-20
6. Schmidt D, Mol A, Odermatt B, Neunschwander S, Breymann C, Gossi M, Genoni M, Zund G and Hoerstrup S. (2006). Engineering of biologically active living heart valve leaflets using human umbilical cord derived progenitor cells. Tissue Engineering 12(11):3223-3232
7. Korbling M, Robinson S, Estrov Z, Champlin R and Shpall E. (2005) Umbilical cord blood derived cells for tissue repair. Cytotherapy 7(3):258-261
8. Denner L, Bodenburg Y, Zhao J, Howe M, Cappo J, Tilton R, Copland J, Forraz N McGuckin C and Urban R. (2007) Direct engineering of umbilical cord blood stem cells to produce C-peptide and insulin. Cell Proliferation 40(3):367-80.
9. Li S, Sun Z, Lu G, Guo X, Zhang Y, Yu W, Wang W, Ma X. (2009). Microencapsulated UCB cells repair hepatic injury by intraperitoneal transplantation. Cytotherapy 11(4):1-9.
10. Yu G, Borlongan C, Stahl C, Hess D, Ou Y, Kaneko Y, Yu S, Yang T, Fang L and Xie X. (2009). Sytemic deliver of umbilical cord blood cells for stroke therapy: a review. Restorative and Neurology and Neuroscience 27(1):41-54.
11. Cho S, Yang M, Yim S, Park J, Eom Y, Jang I, Kim H, Park J, Kim H, Lee B, Park C, Kim Y. (2008) Neurally Induced umbilical cord blood cells modestly repair injured spinal cords. Neuroreports 19(13):258-61
12. Koike N, Adachi Y, Minamino K, Iwasaki M, Nakano K, Koike Y, Yamada H, Mukaide H, Shigematsu A, Mizokami T, Matsumura M, Ikehara S. (2007). Human cord blood cells can differentiate into retinal nerve cells. Acta Neurology Exp 67(4):359-65.

1. Geissler K, Geissler W, Hinterberger W, Lechner K, Wurnig P. (1986) Circulating committed and pluripotent haematoopoietic progenitor cells in infants. Acta Heamatologica 75(1):18-22
http://www.ncbi.nlm.nih.gov/pubmed/3088881
Circulating CFU-GM, BFU-E and CFU-MIX were assayed in 21 infants aged between 1 day and 44 weeks. Compared to 15 adults, progenitor cells of all types were increased until 10 weeks following birth and approached the respective ranges of adults thereafter. The mean increases of progenitor cells in infants aged between 1 day and 10 weeks were 26-fold for CFU-GM, 7-fold for BFU-E and 5-fold for CFU-MIX. Our results demonstrate that not only committed progenitor cells (CFU-GM, BFU-E), but also early progenitor cells with the capacity for self-renewal (CFU-MIX), are increased in early infancy. These data further support the hypothesis that high levels of blood progenitor cells in very early stages of life reflect the colonization process of developing bone marrow by circulating progenitor cells and demonstrate the terminal phase of this process during the first 10 weeks after birth.

2. Ballen KK (2005) New trends in umbilical cord blood transplantation. Blood 105:3786-3792
http://www.ncbi.nlm.nih.gov/pubmed/15677563
Massachusetts General Hospital, 100 Blossom St, Cox 640, Boston, MA 02114, USA.

Since the first report of a successful umbilical cord blood transplantation in 1988, there has been great interest in the use of cord blood as an alternative stem cell source to treat cancer and genetic diseases. More than 4000 cord blood transplantations have been performed worldwide. In this review, the scientific rationale for this therapy, as well as related preclinical studies, cord blood banking issues, and ethical concerns, will be addressed. Results of studies in both pediatric and adult transplantation will be discussed. Finally, new indications for cord blood use and emerging technologies will be addressed.

3. Ruhil S, Kumar V and Rathee P. (2009) Umbilical Cord Stem Cells: an overview. Current Pharmaceutical Biotechnology 10(3):327-34
http://www.ncbi.nlm.nih.gov/pubmed/19355943
Advanced Center for Biotechnology, Maharshi Dayanand University, Rohtak, India.

In recent years, human umbilical cord blood (HUCB) has emerged as an attractive tool for cell-based therapy. Although at present the clinical application of human umbilical cord blood is limited to the fields of hematology and oncology, a rising number of studies show potential for further application in the treatment of non-hematopoietic diseases. Stem cells (SC) from umbilical cord blood (UCB) are now a new reliable alternative to treat different blood diseases, if the samples are frozen at the moment of birth. This procedure is an easy and safe way to preserve genetic materials for future therapeutic uses. It can be used as alternative to bone marrow. Human umbilical cord blood, with its real abundance, simple collection procedure and no serious ethical dilemmas, represents a valuable alternative to the use of other stem cell sources. The aim of this article is to review the literature on human umbilical cord blood (HUCB) and to assess its eventual usability in the treatment of diseases.

4. David Harris and Ian Rogers. (2008) Umbilical Cord Blood: a unique source of pluripotent stem cells for regenerative medicine. Current Stem Cell Research and Therapy 2(4):301-9
http://www.ncbi.nlm.nih.gov/pubmed/18220914
Department of Immunobiology, 1501 N. Campbell Avenue, LSN 643, University of Arizona, Tucson, AZ 85724, USA.

It is estimated that almost 1 in 3 individuals in the United States might benefit from regenerative medicine therapy. Unfortunately, embryonic stem (ES) cell therapies are currently limited by ethical, political, biological and regulatory hurdles. Thus, for the foreseeable future, the march of regenerative medicine to the clinic will depend upon the development of non-ES cell therapies. Current sources of non-ES cells easily available in large numbers can be found in the bone marrow, adipose tissue and umbilical cord blood. Each of these types of stem cells has already begun to be utilized to treat a variety of diseases. This review will show that cord blood (CB) contains multiple populations of ES-like and other pluripotential stem cells, capable of giving rise to hematopoietic, epithelial, endothelial, and neural tissues both in vitro and in vivo. Cumulatively, the identification and isolation of these populations of pluripotent stem cells within cord blood represents a scientific breakthrough that could potentially impact every field of medicine, via their use in regenerative medicine. Thus, CB stem cells are amenable to treatment of a wide variety of diseases including cardiovascular, hepatic, ophthalmic, orthopaedic, neurological and endocrine diseases.

5. Hutson EL, Boyer S, Genever PG. (2005) Rapid isolation, expansion and differentiation of osteoprogenitors from full-term cord blood. Tissue Engineering 11(9-10):1407-20
http://www.ncbi.nlm.nih.gov/pubmed/16259596
Biomedical Tissue Research, Department of Biology, University of York, York, United Kingdom.

There is an urgent clinical requirement for appropriate bone substitutes that can be used for the repair and regeneration of diseased or damaged skeletal tissues. Cell-sourcing limitations in particular have affected progress, largely because of the shortage of accessible tissues capable of yielding sufficient numbers of viable osteoprogenitor cells. Previous work has suggested that umbilical cord blood (UCB) contains circulating progenitor cells (mesenchymal stem cells) capable of osteogenic differentiation, although a comparable number of reports refute this claim. From a screen of more than 20 different culture conditions, we have identified an optimal, simple, and reliable technique to generate, from full-term human UCB, stromal cells with the ability to undergo rapid osteogenic differentiation. By comparing different sorting and culture strategies, we demonstrated that early exposure of mononuclear UCB cells to medium conditioned by osteoblastic cells in the presence of osteogenic supplements and human plasma, markedly increased the frequency of stromal cell growth, the rate of osteogenic differentiation, and their attachment to and spreading on calcium phosphate scaffolds. These findings suggest that full-term UCB may act as an appropriate source of osteoprogenitor cells, which will impact significantly on the development of autologous tissue-engineered bone constructs.

6. Schmidt D, Mol A, Odermatt B, Neunschwander S, Breymann C, Gossi M, Genoni M, Zund G and Hoerstrup S. (2006). Engineering of biologically active living heart valve leaflets using human umbilical cord derived progenitor cells. Tissue Engineering 12(11):3223-3232
http://www.ncbi.nlm.nih.gov/pubmed/17518636
Department of Surgical Research and Clinic for Cardiovascular Surgery, University Hospital and University of Zurich, Zurich, Switzerland.

This study demonstrates the engineering of biologically active heart valve leaflets using prenatally available human umbilical cord-derived progenitor cells as the only cell source. Wharton's Jelly-derived cells and umbilical cord blood-derived endothelial progenitor cells were subsequently seeded on biodegradable scaffolds and cultured in a biomimetic system under biochemical or mechanical stimulation or both. Depending on the stimulation, leaflets showed mature layered tissue formation with functional endothelia and extracellular matrix production comparable with that of native tissues. This demonstrates the feasibility of heart valve leaflet fabrication from prenatal umbilical cord-derived progenitor cells as a further step in overcoming the lack of living autologous replacements with growth and regeneration potential for the repair of congenital malformation.

7. Korbling M, Robinson S, Estrov Z, Champlin R and Shpall E. (2005) Umbilical cord blood derived cells for tissue repair. Cytotherapy 7(3):258-261
http://www.ncbi.nlm.nih.gov/pubmed/16081352
Department of Blood and Marrow Transplantation, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Hematopoietic tissue-derived cells, including stem cells, have been shown to generate solid organ tissue-specific cells. Besides bone marrow and peripheral blood, umbilical cord blood (UCB) has the advantage of being an easily accessible stem cell source provided as a banked cell product. Using the xenogeneic human into NOD/SCID mouse stem cell transplant model preliminary data suggest UCB-derived tissue-specific cells generated in liver, pancreas, CNS and endothelium. In a clinical sex-mismatched UCB transplant setting Y-positive, UCB-derived gastrointestinal epithelial cells and CNS-specific cells have been identified in female patients. The potential therapeutic use of UCB cells for tissue repair is, however, limited by a low total stem cell number available and by HLA-disparity.

8. Denner L, Bodenburg Y, Zhao J, Howe M, Cappo J, Tilton R, Copland J, Forraz N McGuckin C and Urban R. (2007) Direct engineering of umbilical cord blood stem cells to produce C-peptide and insulin. Cell Proliferation 40(3):367-80.
http://www.ncbi.nlm.nih.gov/pubmed/17531081
Stark Diabetes Center and McCoy Diabetes Mass Spectrometry Research Laboratory, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555-1060, USA.

OBJECTIVES: In this study, we investigated the potential of umbilical cord blood stem cell lineages to produce C-peptide and insulin. MATERIALS AND METHODS: Lineage negative, CD133+ and CD34+ cells were analyzed by flow cytometry to assess expression of cell division antigens. These lineages were expanded in culture and subjected to an established protocol to differentiate mouse embryonic stem cells (ESCs) toward the pancreatic phenotype. Phase contrast and fluorescence immunocytochemistry were used to characterize differentiation markers with particular emphasis on insulin and C-peptide. RESULTS: All 3 lineages expressed SSEA-4, a marker previously reported to be restricted to the ESC compartment. Phase contrast microscopy showed all three lineages recapitulated the treatment-dependent morphological changes of ESCs as well as the temporally restricted expression of nestin and vimentin during differentiation. After engineering, each isolate contained both C-peptide and insulin, a result also obtained following a much shorter protocol for ESCs. CONCLUSIONS: Since C-peptide can only be derived from de novo synthesis and processing of pre-proinsulin mRNA and protein, we conclude that these results are the first demonstration that human umbilical cord blood-derived stem cells can be engineered to engage in de novo synthesis of insulin.

9. Li S, Sun Z, Lu G, Guo X, Zhang Y, Yu W, Wang W, Ma X. (2009). Microencapsulated UCB cells repair hepatic injury by intraperitoneal transplantation. Cytotherapy 11(4):1-9.
http://www.ncbi.nlm.nih.gov/pubmed/19701829
Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.

Background aims Umbilical cord blood (UCB) cells are an attractive choice in cytotherapy and represent an alternative to hepatocytes. The aim of this study was to investigate the feasibility of using the technique of microencapsulation to study the differentiation and function of UCB cells in an injured liver model and the potential of encapsulated UCB cells for use in the reversal of hepatic injury. Methods UCB cells were isolated from fresh human UCB, encapsulated using the alginate-poly-lysine-alginate method and transplanted intraperitoneally into liver-injured mice induced by CCl(4). Encapsulated UCB cell growth, viability and differentiation in vivo were detected. For evaluating the recovery of injured liver tissues, serum aminotransferases and liver histology were assessed. Results Encapsulated UCB cells showed better growth behavior after being implanted. Under conditions favoring differentiation in vivo, the expression of alpha-fetoprotein (AFP) and albumin (ALB) and urea synthesis were detected in a time-dependent manner. Serum aminotransferases were decreased after transplantation of encapsulated UCB cells into injured mice, and damage to the histologic structure of the liver was reduced. Conclusions The cell microencapsulation system provides a novel approach for learning more about the differentiation and function of UCB cells in vivo.Transplantation of encapsulated UCB cells can enhance recovery of CCl(4)-injured mouse liver. These observations suggest potential as an alternative to hepatocyte transplantation for cellular therapy of liver failure.

10. Yu G, Borlongan C, Stahl C, Hess D, Ou Y, Kaneko Y, Yu S, Yang T, Fang L and Xie X. (2009). Sytemic deliver of umbilical cord blood cells for stroke therapy: a review. Restorative and Neurology and Neuroscience 27(1):41-54.
http://www.ncbi.nlm.nih.gov/pubmed/19164852
Department of Cardiology, Xiangya Hospital, Southern Central University, Changsha, PR China.

PURPOSE: This review paper summarizes relevant studies, discusses potential mechanisms of transplanted cell-mediated neuroprotection, and builds a case for the need to establish outcome parameters that are critical for transplantation success. In particular, we outline the advantages and disadvantages of systemic delivery of human umbilical cord blood (HUCB) cells in the field of cellular transplantation for treating ischemic stroke. METHODS: A MEDLINE/PubMed systematic search of published articles in peer-reviewed journals over the last 25 years was performed focusing on the theme of HUCB as donor graft source for transplantation therapy in neurological disorders with emphasis on stroke. RESULTS: Ischemic stroke remains a leading cause of human death and disability. Although stroke survivors may gain spontaneous partial functional recovery, they often suffer from sensory-motor dysfunction, behavioral/neurological alterations, and various degrees of paralysis. Currently, limited clinical intervention is available to prevent ischemic damage and restore lost function in stroke victims. Stem cells from fetal tissues, bone marrow, and HUCB has emerged in the last few years as a potential cell transplant cell source for ischemic stroke, because of their capability to differentiate into multiple cell types and the possibility that they may provide trophic support for cell survival, tissue repair, and functional recovery. CONCLUSION: A growing number of studies highlight the potential of systemic delivery of HUCB cells as a novel therapeutic approach for stroke. However, additional preclinical studies are warranted to reveal the optimal HUCB transplant regimen that is safe and efficacious prior to proceeding to large-scale clinical application of these cells for stroke therapy.

11. Cho S, Yang M, Yim S, Park J, Eom Y, Jang I, Kim H, Park J, Kim H, Lee B, Park C, Kim Y. (2008) Neurally Induced umbilical cord blood cells modestly repair injured spinal cords. Neuroreports 19(13):258-61
http://www.ncbi.nlm.nih.gov/pubmed/18695504
Department and Research Institute of Rehabilitation Medicine, Brain Research Institute and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Umbilical cord blood (UCB) is known to have stem/progenitor cells. We earlier showed that novel progenitors could be isolated from cryopreserved human UCB with high efficiency. The multipotent progenitor cells were induced to differentiate into neural-lineage cells under the appropriate condition. In this study, we confirmed these neurally induced progenitor cells (NPCs), containing higher quantities of nerve growth factor, promoted functional recovery in rats with spinal cord injury (SCI). Sprague-Dawley rats with SCI achieved a modest improvement in locomotor rating scale until 10 weeks after transplantation of the NPCs. SCI rats treated with NPCs also showed somatosensory-evoked potentials were recovered, and grafted cells especially exhibited oligodendrocytic phenotype around the necrotic cavity. These findings suggest that UCB-NPCs might be a therapeutic resource to repair damaged spinal cords.

12. Koike N, Adachi Y, Minamino K, Iwasaki M, Nakano K, Koike Y, Yamada H, Mukaide H, Shigematsu A, Mizokami T, Matsumura M, Ikehara S. (2007). Human cord blood cells can differentiate into retinal nerve cells. Acta Neurology Exp 67(4):359-65.
http://www.ncbi.nlm.nih.gov/pubmed/18320714
First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka 570-8506, Japan.
Retinal degeneration and dystrophy are the major causes of blindness in the developed world. It has been reported that human cord blood cells (HCBCs) can differentiate into neuron-like cells in vitro. We have recently demonstrated that bone marrow cells (BMCs) of both mice and rats can differentiate into retinal nerve cells (RNCs). In the present study, we show the differentiation capacity of HCBCs into RNCs in vivo. We transplanted lineage-negative HCBCs into the subretinal space of severe combined immunodeficiency (SCID) mice. Two weeks after the transplantation, some of the transplanted cells expressed human nestin, human MAP2, human neuron specific enolase (NSE), beta-III tubulin and also rhodopsin. These results indicate that HCBCs can differentiate into RNCs and suggest that our new strategy could be used for the regeneration of retinal nerve cells in degenerative or dystrophic diseases.