BSP :: Current Stem Cell Research & Therapy Home Page

Contents

Application of stem cells in cardiology: Where we are and where we are going Pp. 1-11
José Marín-García and Michael J. Goldenthal
[Abstract] [Full Text Article]

The Importance of Adipose-Derived Stem Cells and Vascularized Tissue Regeneration in the Field of Tissue Transplantation Pp. 13-20
Rei Ogawa
[Abstract] [Full Text Article]

Mesenchymal stem cell-based HLA-independent cell therapy for tissue engineering of bone and cartilage Pp. 21-27
Philipp Niemeyer, Ulf Krause, Philip Kasten, Peter C. Kreuz,Philipp Henle, Norbert P. Südkamp, Alexander Mehlhorn
[Abstract] [Full Text Article]

Dose-intensive chemotherapy with stem cell support as a treatment strategy for bone and soft-tissue sarcomas Pp. 29-35
Bernd Kasper, Anthony D. Ho, Gerlinde Egerer
[Abstract] [Full Text Article]

Respiratory stem cells and progenitors: overview, derivation, differentiation, carcinogenesis, regeneration, and therapeutic application Pp. 37-46
Shibichakravarthy Kannan and Min Wu
[Abstract] [Full Text Article]

Cryopreserving Human Peripheral Blood Progenitor Cells Pp. 47-54
Anne Margrethe Bakken
[Abstract] [Full Text Article]

Understanding stem cell-mediated brain repair through neuroimaging Pp. 55-63
Mike Modo
[Abstract] [Full Text Article]

Screening the brain: molecular fingerprints of neural stem cells Pp. 65-77
Martin H. Maurer and Wolfgang Kuschinsky
[Abstract] [Full Text Article]

Neural Stem Cells - A Promising Potential Therapy for Brain Tumors Pp. 79-84
Irvin, Dwain; Yuan, Xiangpeng; Tunici, Patricia Yu, John S.
[Abstract] [Full Text Article]

Our Perception of Developmental Plasticity
Esse Est Percipi (to be is to be Perceived)? Pp. 85-94
Nadir Askenasy, Isaac Yaniv, Jerry Stein, Saul J. Sharkis
[Abstract] [Full Text Article]

The stem state: Mesenchymal plasticity as a paradigm Pp. 95-102
Dov Zipori
[Abstract] [Full Text Article]

Intracellular Signaling Pathways Regulating Pluripotency of Embryonic Stem Cells Pp. 103-111
Keisuke Okita and Shinya Yamanaka
[Abstract] [Full Text Article]

Epithelial Stem Cells and Tissue Engineered Intestine Pp. 113-120
Richard M. Day
[Abstract] [Full Text Article]

Dendritic cell therapy for tolerance induction during stem cell transplantation Pp. 121-125
Helen C. O’Neill
[Abstract] [Full Text Article]

Abstracts

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Application of stem cells in cardiology: Where we are and where we are going
José Marín-García and Michael J. Goldenthal

[Full Text Article]

Heart disease including myocardial infarction and ischemia is associated with the irreversible loss of cardiomyocytes and vasculature, both via apoptosis or necrosis. However, the native capacity for the renewal and repair of myocardial tissue is inadequate as have been current therapeutic measures to prevent left ventricular remodeling. Cell transplantation has emerged as a potentially viable therapeutic approach to directly repopulate and repair the damaged myocardium. A detailed analysis and a vision for future progress in stem cell applications, both in research and clinical cardiology is presented in this review, highlighting the use of a wide spectrum of stem/progenitor cell types including embryonic or fetal stem cells, myoblasts, and adult bone marrow stem cells. An up-to-date comparison of donor cell-types used, and evaluation of the myocardial disorders that might be most amenable to stem cell therapy are discussed. The roles that myocardial cell fusion and transdifferentiation play in stem cell transplantation, the specific shortcomings of available technologies, and recommendations for practical ways that these concerns might be overcome are also presented.

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The Importance of Adipose-Derived Stem Cells and Vascularized Tissue Regeneration in the Field of Tissue Transplantation
Rei Ogawa

[Full Text Article]

The importance of stem cells in regenerating or repairing damaged or diseased tissues is well established, but three factors have to be considered in employing stem cells clinically. The first is how to harvest, handle, and multiply them non-invasively, easily, and effectively. From this standpoint, adipose-derived stem cells are considered to be the best to work with among mesenchymal stem cells; since they were first reported in 2001, their pluripotency, proliferative efficiency, and low donor morbidity have been amply confirmed. The second factor is how to differentiate stem cells into the required cells and use them effectively to construct three-dimensional tissues; here, tissue-specific scaffolds and signaling systems are essential. The third factor is how to ensure survival of the differentiated cells and regenerated tissues. Regenerated tissues need to contain vascular systems to allow both the tissues themselves and the differentiated cells to survive. Thus, we believe that the vascularization of regenerated tissues will be an important field of research in the near future. In this paper, we focus on adipose-derived stem cells and vascularized tissue regeneration within the context of tissue transplantation.

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Mesenchymal stem cell-based HLA-independent cell therapy for tissue engineering of bone and cartilage
Philipp Niemeyer, Ulf Krause, Philip Kasten, Peter C. Kreuz,Philipp Henle, Norbert P. Südkamp, Alexander Mehlhorn

[Full Text Article]

Mesenchymal stem cells (MSC) can be obtained from human bone marrow aspirates and, thanks to their differentiation potential and excellent in vitro culture properties, represent an attractive cell line for the regeneration of mesenchymal tissue. Both in vitro and in vivo, they can differentiate into cartilage, bone, tendons and fat cells, and—in contrast to embryonic stem cells—they are not under ethical scrutiny. Cultured on three-dimensional scaffolds according to the tissue engineering concept, they have already been successfully employed for reconstruction of mesenchymal tissues in numerous studies involving both small and large animal models. Recently, immunological properties of hMSC have been investigated by several groups. On the basis of the available literature, hMSC have to be referred to as immune privileged, and they seem to be available for HLA-independent cell transplantation. While clinical MSC transplantation has also been successfully performed in pilot studies in humans, numerous points still remain to be clarified, underscoring the need for further intensive research before large-scale clinical application can be contemplated. Only then can it be shown whether the associated high expectations are justified.

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Dose-intensive chemotherapy with stem cell support as a treatment strategy for bone and soft-tissue sarcomas
Bernd Kasper, Anthony D. Ho, Gerlinde Egerer

[Full Text Article]

Whether high-dose chemotherapy with stem cell support improves the long-term outcome for patients with bone and soft-tissue sarcoma is debatable and controversial. Prognosis of patients with unresectable or advanced metastatic sarcoma remains poor with a disease-free survival at 5 years less than 10%; treatment is generally considered to be palliative. Doxorubicin, epirubicin and ifosfamide are the most active single agents with response rates above 20%. Although drug combinations result in higher response rates, superiority against single agent chemotherapy in terms of survival could not have been demonstrated yet. As a dose-response relationship has been shown for the anthracyclines and especially for ifosfamide, high-dose chemotherapy with stem cell support has been evaluated by several investigators. However, all studies were not randomized, comprised small patient numbers and included heterogeneous histological subtypes of soft-tissue sarcomas. Nevertheless, higher doses of chemotherapy result in higher remission rates, which could correlate with longer survival. Well-designed randomized trials should be performed.

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Respiratory stem cells and progenitors: overview, derivation, differentiation, carcinogenesis, regeneration, and therapeutic application
Shibichakravarthy Kannan and Min Wu

[Full Text Article]

Recently, research of stem cells has garnered great attention and has shown promise by changing the view of traditional therapeutics, with broad impact on gene therapy, carcinogenesis, organ development, tissue injury, regeneration and almost all aspects of the life cycle and all living systems. A century’s scientific progress has significantly improved controls for infectious diseases and many other disorders. However, many remaining problems (i.e. cancer, AIDS, diabetes, Parkinson’s disease and Marburg infection) appear to be even harder than those that have already been solved. In particular, respiratory stem cell research has been less active and has moved more slowly than that of many other organs. This is probably due to the complexity of the lung and airway system, particularly owing to the many types of cells (>40), unique structures and functions, and technical difficulty in analyzing this system at the genetic, biochemical, molecular and cellular level. Compared with other epithelial cells (i.e., gastrointestinal epithelium), respiratory epithelia have a very low turnover rate and minimal regenerative activity. This review will discuss the current state of pulmonary stem cells, their origin, development, differentiation, and regenerative application, with a particular focus on potential impact on cancer development and lung injury repair.

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Cryopreserving Human Peripheral Blood Progenitor Cells
Anne Margrethe Bakken

[Full Text Article]

High-dose chemotherapy followed by autologous peripheral blood progenitor cell (PBPC) transplantation is used in the treatment of chemosensitive malignancies. Cryopreservation of PBPC in 10% dimethyl sulfoxide (DMSO) has been the standard procedure in most institutions. Infusion of PBPC cryopreserved with DMSO can be associated with toxic reactions such as vomiting, cardiac dysfunction, anaphylaxia and acute renal failure. The grade of toxicity experienced by patients is related to the amount of DMSO present in the PBPC. Cryopreservation with lower DMSO concentrations would be expected to reduce the toxicity. In recent studies done with PBPC cells cryopreserved with 5%, 4% and 2% DMSO, using 10% DMSO as a reference control, CD34⁺ cells were investigated for preservation of viability, apoptosis, and necrosis. Also preservation of mature colony-forming (CFU) cells, specifically mature myeloid, erythroid progenitors, CFU-megakaryocytes and long-term culture-initiating cells (LTC-ICs) were investigated, using 5% and 10% DMSO as cryoprotectant. All samples were frozen in a rate-controlled programmed freezer and stored in the vapor phase of liquid nitrogen until used. Conclusion: 5% DMSO is the optimal concentration for cryopreserving human PBPC in vitro. Consequently, some hospitals have started using 5% DMSO as cryoprotectant for the autologous PBPC as a standard procedure.

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Understanding stem cell-mediated brain repair through neuroimaging.
Mike Modo

[Full Text Article]

Transplantation of stem cells into the damaged brain can lead to behavioral recovery. However, at present the mechanisms by which these cells exert their beneficial effects are still poorly understood. Survival, migration and differentiation are but a few of the factors that are thought to be involved in stem cell-mediated brain repair. It is hoped that neuroimaging, by MRI and PET, will provide serial in vivo assessments of transplanted cells that can lead to a greater understanding of the mechanisms involved in brain repair.

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Screening the brain: molecular fingerprints of neural stem cells
Martin H. Maurer, Wolfgang Kuschinsky

[Full Text Article]

With the development of high-throughput technologies like microarrays for genomic and transcriptomic analysis, and two-dimensional gel electrophoresis, mass spectrometry, and protein arrays for proteomic analysis, it is possible to monitor the changes in gene or protein expression of several hundreds, or even thousands of molecules simultaneously. Within the last years, these technologies have been applied successfully to stem cell research. One of the aims of stem cell expression profiling is to find specific marker genes or proteins which may determine the "stemness" of these cells. In the current review, we will evaluate the results of genomic, transcriptomic and proteomic approaches to find stem cell markers.

We compare the criteria of "stemness" to recent results in adult neural stem cell research. Neural stem cells have been isolated from various regions of the adult brain. They self-renew and give rise to progeny capable to generate neurons, astrocytes, and oligodendrocytes. Besides morphological differentiation, these cells can integrate into functional neuronal circuits, making them suitable targets for cell replacement strategies. General properties seem to be the responsiveness to growth factors, and the activation of developmental signaling pathways. In conclusion, we suggest that stem cell properties can be specified by global gene or proteomic expression patterns rather than by the analysis of individual genes or proteins.

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Neural Stem Cells - A Promising Potential Therapy for Brain Tumors
Irvin, Dwain; Yuan, Xiangpeng; Tunici, Patricia; Yu, John S.

[Full Text Article]

Brain tumors can be highly aggressive and debilitating for many patients and lead to an untimely death in just a few months. Unfortunately, due to the location of many brain tumors, therapy with ionizing radiation, chemotherapeutic agents and/or surgery has limited rewards. In addition, the probability of totally removing highly infiltrative tumors, particularly gliomas, is extremely low. Currently, these methods rarely provide a cure for many patients. The need for directed targeting and ablation of tumors with minimal damage to nearby healthy tissue has lead to the most recent findings and uses of neural stem cells for therapeutic treatment of brain tumors. Recently, some very promising studies have demonstrated that exogenous neural stem cells have the remarkable ability to migrate very long distances towards sites of metastasis after transplantation. These studies also show that intravascular injections of neural stem cells may lead to preferential migration towards central nervous system tumors. It has also been demonstrated that genetically modified neural stem cells, engineered to produce anti-tumor molecules, upon transplantation, have the ability to migrate towards tumors and reduce tumor mass directly or through a “bystander” effect. Here we review the current literature examining the promise of utilizing genetically modified neural stem cells as vehicles for CNS tumor therapy.

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Our Perception of Developmental Plasticity
Esse Est Percipi (to be is to be Perceived)?
Nadir Askenasy, Isaac Yaniv, Jerry Stein, Saul J. Sharkis

[Full Text Article]

The continuing interest in the biology of stem cells is enhanced by new discoveries surrounding developmental plasticity of both embryonic and adult stem cells. Adoptive transfer of concepts and definitions from the hematopoietic system for the existence of other tissue stem cells suggests inclusion of characteristics such as ability to self-renew and differentiate to functionally reconstitute a tissue/organ of origin. How adequate and accurate are these definitions? Within the great unknown of how these cells function, modulate their gene expression patterns and respond to extrinsic signals, it is apparent that there are numerous levels of stemness. We may envision a scale of developmental flexibility. At one end of the scale are positioned the embryonic stem cells, and at the other end are positioned partially-differentiated, differentiation restricted (committed) tissue/organ stem cells. There is evidence that some stem cells in the adult are pluripotent, thus positioned close to the embryonic end of the stem scale. It is uncertain yet to what extent stem cells can move back and forth along the stem scale.

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The stem state: Mesenchymal plasticity as a paradigm
Dov Zipori

[Full Text Article]

The mesenchyme is a remarkably plastic tissue in the embryo. Recent studies led to the discovery of mesenchymal cells in the adult organism that can differentiate in vitro into unexpected directions, beyond the well known ability of the mesenchyme to give rise to mesodermal derivatives. These studies highlighted the plastic nature of the mesenchyme, also beyond the embryonic developmental stage. This review discusses the possible functions of the mesenchyme in the adult and the reason for the maintenance of plasticity throughout mammalian life. The properties of the mesenchymal cells clearly exemplify the stem state concept; cells whether early or late in the differentiation cascade may assume a stem state that entails high plasticity.

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Intracellular Signaling Pathways Regulating Pluripotency of Embryonic Stem Cells
Keisuke Okita and Shinya Yamanaka

[Full Text Article]

The cytokine LIF and its downstream effector STAT3 are essential for maintenance of pluripotency in mouse ES cells. The requirement for the transcription factor Oct3/4 for ES cell pluripotency is also well-documented. However, LIF is not involved in self-renewal of human ES cells, suggesting that other pathways must play an important role in this process. The importance of other signal transduction pathways, including BMP and Wnt signalings, as well as novel transcription factors such as Nanog, is now being recognized. We will review the rapid progress that has been made in identifying and dissecting the intracellular signaling pathways that contribute to self-renewal of pluripotent mouse and human ES cells.

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Epithelial Stem Cells and Tissue Engineered Intestine
Richard M. Day

[Full Text Article]

The intestinal mucosa has an amazing regenerative capacity, enabling rapid restoration of its physiological functions following injury. The ability to do this resides with the epithelial stem cells located within glandular invaginations in the mucosal surface. Recent advances in the isolation and characterization of epithelial stem cells has paved the way for exploring novel therapeutic approaches for gastrointestinal disease. Possible stem cell-based therapy of gastrointestinal disorders range from the repair of damaged mucosa through to tissue engineering of artificial intestinal constructs for patients with short bowel syndrome. Before these benefits are realized further information is required on the biological characteristics of intestinal stem cells, their interactions with surrounding cells, and the environment in which they reside. This includes discovering markers to assist in the identification and purification of stem cell populations and techniques to manipulate the cells both in vivo and in vitro. Because intestinal transplantation for patients still represents a significant challenge, it is hoped that one day a tissue-engineered intestine will provide a feasible option for patients with short bowel syndrome. This review aims to introduce the reader to the main characteristics of epithelial stem cells and provide an overview of the current status of intestinal tissue engineering and the problems still being faced.

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Dendritic cell therapy for tolerance induction during stem cell transplantation
Helen C. O’Neill

[Full Text Article]

With rapid progress in identification of a variety of adult stem cells, there is an urgent need for basic studies on immunomodulatory protocols relevant to stem cell transplantation. There are now new possibilities for immunomodulation invoking the function of DC in the induction of tolerance. This paper addresses the application of DC immunotherapy for establishing and maintaining peripheral tolerance to stem cell or tissue allografts. While recent approaches target immature DC and their role in peripheral tolerance, many questions can be raised about the tolerogenic properties of those cells and the clinical feasibility of their use. Procedures published to date for preparation of DC differ significantly in terms of the source of cells and methods for culture and expansion of immature, apparently tolerogenic DC. With evidence for tolerogenicity associated with all classes or lineages of DC, the hypothesis is advanced that the tolerogenicity of DC is determined during hematopoiesis and may be best established by immunotherapy using DC progenitors. It is expected that peripheral tolerance and central or thymic-based tolerance may complement each other as two essential mechanisms for transplantation tolerance since different clinical situations may invoke the need for different procedures for tolerance induction.