9. .Concise review: recent advances on the significance of stem cells in tissue regeneration and cancer therapies. Mimeault M, Batra SK. Stem Cells. 2006;24:2319-45.

The title is misleading because this is an extensive review (26 pages) which must be read in the original because it is too comprehensive to be well summarized here so that only an outline can be provided.

There is great interest in the biology of adult stem cells because of their capacity to self-renew and their high plasticity. These traits enable adult stem cells to produce diverse mature cell progenitors that actively participate in the maintenance of homeostatic processes by replenishing the cells that repopulate the tissues/organs during a lifespan and regenerate damaged tissues during injury. In general, embryonic, fetal, and adult stem cells show several common functional properties including their high self-renewal capacity and potential to generate differentiated cell progenitors of different lineages under simplified culture conditions in vitro and after transplantation in the host in vivo. This suggests that they may contribute to the regeneration of damaged tissues. Therefore, the use of stem cells and their progenitors is a promising strategy in cellular and genetic therapies for multiple degenerative disorders, as well as adjuvant immunotherapy for diverse aggressive cancer types. Parkinson and Alzheimer diseases, muscular degenerative disorders, chronic liver and heart failures, and type 1 and 2 diabetes, as well as skin, eye, kidney, and hematopoietic disorders could be treated by the stem cell-based therapies.

The authors list possible therapeutic applications of embryonic, umbilical cord blood and adult stem cell progenitors in a detailed table. The authors then report the structural and functional features of embryonic, umbilical cord and adult stem cells and their niches, as well as the procedures that are used for their differentiation into particular cell lineages in vitro and in vivo. A detailed description is provided of embryonic stem cells, amniotic epithelial cells, fetal stem cells, umbilical cord stem cells, and adult stem cells. Next the authors discuss adult stem cells of endodermal origin (pulmonary epithelial stem cells, GI tract stem cells and urogenital stem cells), and then review adult stem cells of mesodermal origin (hematopoietic stem cells, stromal stem cells, cardiac stem cells) and stem cells of ectodermal origin (neural stem cells, skin stem cells, ocular stem cells).

The possibility of using stem cells and their more differentiated progenitors to treat numerous degenerative disorders has stimulated great interest in developing safe transplantable sources of stem cells that are unable to form teratomas but are able to repopulate damaged tissues. The authors report the recent advances on the more promising stem cell-based strategies that have been developed for the treatment of numerous degenerative disorders and aggressive cancer types. This discussion includes a review of regenerative medicine in pancreatic diseases, CNS disorders and diseases, Parkinson and Alzheimer disease, spinal cord injuries, ocular disorders, and blood and immune system disorders. Finally, the role of stem cells in cancer therapies is discussed including the use of high-dose cancer therapy plus HSCs.

The authors conclude with a hopeful note suggesting that future works should establish molecular changes occurring in adult stem cells and their progenitors during tissue repair and etiopathogenesis. Hence, these further studies could lead to the development of more effective treatments for numerous genetic and degenerative disorders by cell replacement. Moreover, the identification of specific markers and targeting distinct tumorigenic cascades in cancer progenitor cells should also contribute to developing novel early detection methods and combination therapies for diverse aggressive and lethal cancers derived from the malignant transformation of adult stem cells.

10. Clinical trials with adult stem/progenitor cells for tissue repair: let's not overlook some essential precautions. Prockop DJ, Olson SD. Blood. 2007;109:3147-51.

This is a thoughtful “Perspective” discussing the current wave of enthusiasm for clinical trials in which adult stem/progenitor cells are used to repair tissues. In theory, adult stem/progenitor cells may provide a therapy for an almost unlimited number of serious and currently untreatable diseases. In the wave of enthusiasm, however, several essential precautions are not being fully addressed.

As with most dramatically new therapies, the data from basic studies and from animal models are never as conclusive as one would like. The best one can say is that the data are encouraging enough to justify carefully controlled trials in patients in whom the risks can be fully justified.

Currently, the largest number of clinical trials is in patients with heart disease. Here, a confusing variety of cells and strategies for different syndromes have been tested and are outlined in an extensive table in the publication. Most of the trials using bone marrow cells have reported improvements in cardiac function. However, the number of patients enrolled in well-controlled trials is still limited.

Potential dangers of such trials are indicated: One such danger is that the clinical trials will be performed without appropriate controls or without well-defined end points. This danger seems particularly apparent in trials concerning acute myocardial infarction in which there is great variability in the size and location of the lesions, the outcomes are difficult to predict, and different parameters have been used to assess heart function.

Ironically, a second potential risk arises from the striking ability of stem/progenitor cells to enhance repair of tissues and to suppress immune reactions: several reports demonstrated that multipotent mesenchymal stem cells (MSCs) will enhance the growth of cancers in mice. Therefore, there is a risk that administering MSCs or similar cells will enhance the growth of a previously undetected cancer in a patient. Also, stem/progenitor cells that are extensively expanded in culture may themselves generate tumors in patients.

A further danger is posed by cells that are injected in high concentrations into tissues. Such cells can form aggregates with the potential to differentiate their own microenvironment to form nodules of bone or other undesirable structures.

Finally, researchers currently face the danger of generating a great deal of confusion by clinical trials in which the cells used are not adequately characterized. Certainly, researchers will all be sorry if clinical trials with adult stem/progenitor cells do not incorporate some of the simple and essential precautions that can prematurely close down new therapies.

11. Differentiation of umbilical cord blood-derived multilineage progenitor cells into respiratory epithelial cells. Berger MJ, Adams SD, Tigges BM, Sprague SL, Wang XJ, Collins DP, McKenna DH. Cytotherapy. 2006; 8:480-487.

The authors report differentiation of human UCB-derived multipotent stem cells, termed multilineage progenitor cells (MLPC), into respiratory epithelial cells (i. e. type II alveolar cells).

Using a cell separation medium (PrepaCyte-MLPC; BioE Inc. ) and plastic adherence, MLPC were isolated from four of 16 UCB units and expanded. Cultures were grown to 80% confluence in mesenchymal stromal cell growth medium (MSCGM; Cambrex BioScience) prior to addition of small airway growth medium (SAGM; Cambrex BioScience), an airway maintenance medium. Following a 3-8-day culture, cells were characterized by light microscopy, transmission electron microscopy, immunofluorescence and reverse transcriptase (RT)-PCR.

MLPC were successfully differentiated into type II alveolar cells (four of four mixed lines; two of two clonal lines). Differentiated cells were characterized by epithelioid morphology with lamellar bodies. Both immunofluorescence and RT-PCR confirmed the presence of surfactant protein C, a protein highly specific for type II cells.

The authors state that, to the best of their knowledge, this is the first time human non-embryonic multipotent stem cells have been differentiated into type II alveolar cells. Further studies to evaluate the possibilities for both research and therapeutic applications are necessary.

12. Characterizing donor-derived cells in nonhematopoietic tissue. Ramakrishnan A, Shi D, Torok-Storb B. Biol Blood Marrow Transplant. 2006; 12:990-992.

The concept that adult stem cells harvested from marrow may differentiate into both hematopoietic and nonhematopoietic tissues is appealing and, if true, would have significant therapeutic potential. Numerous reports documenting adult stem cell plasticity have been published in the last decade, in which authors reported differentiation of bone marrow stem cells into muscle, nerve, liver, lung and intestinal epithelium. The data in these reports were obtained primarily from sex-mismatched transplantation studies in which immunohistochemistry (IHC) for tissue-specific antigens was combined with fluorescence in situ hypridization (FISH) for sex chromatin to identify donor-derived cells in nonhematopoietic tissues. However, the validity of these findings has remained controversial.

The authors sought to address this controversy and, to that end, obtained liver and intestinal tissue from a female patient at day 109 after allogeneic stem cell transplantation from a male donor. They prepared slides and on the same sections combined IHC for the CD45 antigen to distinguish cells from the hematopoietic lineage and FISH for X and Y chromatin to distinguish between donor and host. Under high power, 200 nuclei were counted; the donor chromatin signal was, with few exceptions, always associated with CD45. Similar findings were obtained in the tissues of 2 other females who had also undergone sex-mismatched transplantation. The only exceptions were a few cells detected in liver sections that were CD45-negative and contained 2 X chromosomes and 1 Y chromosome, suggesting full fusion.

These observations, together with previous studies in which the authors found no evidence of donor-derived stroma in patients at 0.15-27 years post-allogeneic transplantation, call into question the concept of a totipotent marrow stem cell.

Future studies designed to address this topic should include IHC for CD45 to definitively determine whether a donor signal is associated with a cell derived from the hematopoietic lineage.

13. The Politics and Promise of Stem-Cell Research. Schwartz, RS. N Engl J Med 2006 355: 1189-1191.

In this Perspective on stem cell research, the author who is a deputy editor of the New Eng J Med, points out that the notion that adult stem cells have the same developmental potential as embryonic stem cells, let alone "more promise" is dubious. He also derides some information available on the internet regarding cures of diseases with adult stem cells as "pure hokum." He further insists that anecdotal reports, such as that of a wheel-chair bound patient with multiple sclerosis who received cord blood stem cells and recovered her ability to walk within minutes, are lures used to trap hapless patients into a treatment that has no merit whatsoever. (Also see in News & Issues: "Stem cell treatment warning" and "Patients warned over dangers of untested stem-cell wonder cures".)

Experiments to establish the existence of a pluripotent stem cell in adults are crucial but, currently, there is no clinical evidence of such cells. There had been no prospective trial to test the proposition that adult hematopoietic stem cells can improve the function of a tissue other than bone marrow. However, in the September 21, 2006 issue of the New Eng J Med, three important articles correct this deficiency.

The authors of these three articles merit high praise for carrying out very difficult studies in humans with myocardial infarction. However, the studies are open to two important criticisms: the injected cells were not always rigorously purified hematopoietic stem cells, and they provide no evidence that the injected hematopoietic cells actually settled in the heart and became cardiac myocytes.

Overall, the results of the three studies of a combined total of 376 patients do not promote the use of intracoronary infusions of autologous bone marrow to improve ventricular function. Lunde et al (citation 16) found no significant differences between the control and bone marrow-treated groups in left ventricular function or infarct size; Schächinger et al. (citation 17) and Assmus et al. (citation 18) found small, significant but clinically uncertain improvements in ventricular function in the bone marrow-treated groups.

These three clinical trials will probably not stop the clinical exploitation of patients with promises that bone marrow (or cord blood) can cure almost any chronic disease. It is important to play down promises to the public that the work will produce anything of clinical value in the foreseeable future. We simply don’t know how an embryonic stem cell will behave in a human, and we don’t know whether human marrow contains a pluripotent stem cell that can transdifferentiate. Equally important, we don’t yet know whether research on embryonic stem cells will teach us how to revise the differentiation program of a tissue-specific stem cell, thereby circumventing the need for embryonic cells.

The author makes it abundantly clear that he feels that the delay of medical advances by theological disputes is not in the best interests of the sick and disabled.

14. Bit Player or Powerhouse? China and Stem-Cell Research. Murray F, Spar D. N Engl J Med 2006; 355: 1191-1194.

In this Perspective the authors comment on the state of scientific research in China with particular reference to stem cell research. Both Science and Nature have reported in recent years that China's stem-cell programs had potential, and a delegation from Britain's Department of Trade and Industry concluded in 2004 that Chinese research in the field was already world-class.

The authors visited China in December 2005 to examine the present status and potential for the future of stem-cell related research. They reviewed the physical, financial, and institutional infrastructure; and whether the Chinese were pursuing innovation through different channels from those that prevail in the West. Their conclusion was that China's role in stem-cell research seems marginal. Advantages are less cost for producing goods in China and less onerous constraints on clinical research leading to greater freedom to test treatment protocols and to move laboratory innovations rapidly into a health care setting. The latter advantage is of minimal significance at this moment "since the science of stem cells is still far from being applied" and since greater international collaboration might well prod Chinese scientists into conforming more closely to global standards.

So for the moment, it seems, China's position in stem-cell science is similar to its position in other spheres: it is an up-and-coming player with global ambitions a burgeoning pool of talent and specific assets that derive from its sheer size.

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