Introduction – From Stem Cells to Regenerative Medicine

Summary: Regenerative medicine, a new chapter of medical sciences presents emerging impact on public opinion and politics and challenge to bioethics, philosophy of science and to law in its national and international dimension. All these topics are presented and discussed on the conference  "Stem Cells, the Challenge to Medical Sciences – Bioethical and Legal Controversies" organized by the Medical Division of the Polish Academy of Sciences in April 2004. Original experimental research on the nonembryonal stem cells, including neuronal stem cells, results of clinical application of human stem cells, including umbilical blood cells,  in hematology and leukemia. postinfarction congestive heart cardiology, human skin and epithelium regeneration are presented. Joint debate  by  top experts in medical research and regenerative medicine confronted with specialists in  philosophical, ethical and international legal aspects of stem cells manipulation is presented. In this respect a clear distinction between nonembryonal and embryonal  stem cells is stressed. Hopes on controlled transformation of nonembryonal human ovarian cells into pluripotential stem cells are articulated.

Key words: stem cells, clinical experiment,  medical risk, bioethics, legal aspects.  

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Stem Cells – Great Expectations?

Summary: The therapeutic strategies based on the clinical application of stem cells woke up great expectations in the medical world. The same strategies, however, become a subject for many controversies among scientists, lawyers, clergy, journalists and several other influential lobbies. This paper was presented at a special meeting prepared by Polish Academy of Sciences that was devoted to the ethical problems of stem cell based therapies.  Based on the literature and own experience the author presented his own point of view on this both promising and controversial area of clinical medicine

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Embryonic Versus Somatic Stem Cells in Regenerative Therapy of Brain

Summary: Proponents of embryonic stem cell (SC) research in humans make promises of cure for a multitude diseases based on the assumption that they will be able to proliferate indefinitely in culture and to generate any type of cell of human body. However, this vision does not meet clinical reality which, so far, reached only the level of preclinical experimental research. The same purposes can be realized by the use of multi/pluripotent somatic SC but they are also hampered by serious difficulties in practice and till now have attained only partial clinical success. This review summarize what we currently know about SC of the both types (embryonic versus somatic) with aim to define a major theoretical and practical handicaps delaying the stem cell-based therapies in treatment of human diseases. We point not to ethical or legal issues, although in no doubt also concerning SC research, but exclusively to biological difficulties and hazards which are hardly avoided at presence.  They include an unstable state of human embryonic SC genome which results in cumulating mutations in vitro and disturbing ability to form tumors in vivo. On the other side a limited knowledge about adult SC proliferation kinetics seems to be the main obstacle to achieve unrestricted grow of these cells in culture and thus limits their use in practice. The scientists agree that present achievements are encouraging but future progress will depend on difficult to foresee growing knowledge about basic SC biology.

Key words:  stem cells, embryonic, somatic, brain regeneration.

Embryonic Stem Cells – Potential Utilization in Medicine

Summary: Embryonic stem cells (ESC) are a promising object for research. The potential to differentiate into almost every cell type might be a "dream comes true" for regenerative medicine. This review focuses on discussing the most important characteristics of ESC. The known methods of their derivation are discussed. The prospects of ESC utilization in medicine are reviewed. Moreover some ethical aspects are discussed that influence general acceptation of ESC research.

Key words: embryonic stem cells  

Reprogramming of the Genom of Somatic Cells as an Alternative for the Use of Embryonic Stem Cells

Summary: Because of many ethical and moral problems connected with the use of embryonic stem cells (EC) in medical treatment in some laboratories the research is started  on reprogramming of differentiated somatic cells as skin fibroblast. The aim is to obtain the cells similar if not identical with EC.  This research is far to be completed but if succesfull � will solve many difficulties and problems.

Key words: embryonic stem cells, skin fibroblast.  

Bone Marrow as Source of Circulating CXCR4⁺ Tissue Committed Stem Cells

Summary: Our recent studies, in which we employed chemotactic isolation to an stromal derived factor-1 (SDF-1) gradient combined with real time PCR (RT-PCR) analysis revealed that bone marrow (BM) contains a highly mobile population of CXCR4⁺ cells that express mRNA for various markers of early tissue committed stem cells (TCSC). We found that these CXCR4⁺ TCSC: i) are enriched in BM from young (1–2 month-old) mice and are scarcely detectable in 1-year-old animals, ii) reside in populations of BM-derived non-adherent non-hematopoietic Sca-1⁺ CD45- cells, iii) contain cells expressing mRNA for embryonic/pluripotent transcription factors such as Oct-4, Nanog and Rex-1, iv) are released (mobi  lized) from BM into peripheral blood (PB) during tissue/organ injury and subsequently chemoattracted by an SDF-1 gradient to damaged tissues, and v) finally may play a role in tissue repair/regeneration. Based on this we postulate that the BM is not only a home for hematopoietic stem cells (HSC) but also a �hideout� for already differentiated non-hematopoietic CXCR4⁺ TCSC and we suggest that their presence in BM tissue should be considered before experimental evidence is interpreted simply as trans-differentiation/plasticity of HSC. Furthermore, expression of embryonic transcription factors in CXCR4⁺ TCSC suggests that this population of cells could also contain more primitive pluripotent stem cells. Finally, our observation that the number of TCSC is the highest in BM of young animals and decreases with age provides a novel insight into aging and may explain why the regeneration process becomes less effective in older individuals.

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Application of Autologous Myoblasts in Post-Infarction Heart of Patients with Cardiovascular Insufficiency

Summary: Cardiovascular diseases belong to the community illness of the developed world. It is number one reason of the death among the all groups of patients. Treatment of the heart infarction despite of the progress in this field is still unsatisfactory. Evolutionary, it was omitted a mechanism for self rege  neration of heart while the late infarction disease is only treated symptomatically what dose not prevent a heart remodeling leading to circulatory insufficiency (or death). Application of cell engineering was one of the few methods available for regeneration of irreversibly damaged myocardium. Intensive pre-clinical studies on mice, rats, rabbits, sheep have shown a positive effect of stem cells on improvement of heart contractility and its basic hemodynamic parameters. Applied stem cells mostly originated from muscle tissue reservoir or bone marrow. It is emphasized not full compatibility between endogenous cardiomyocytes and ectopic donor cells. Frequently implanted autologous stem cells to the heart do not induce any adverse reactions, however their electrophysiological coupling and expression of some genes are below the expected values. Despite of this effects, the beneficial features of stem cell application are evident and statistically significant (improvement of heart contractility and ejection fraction). In the clinical Phase I studies (also in own experiments) with application of myoblasts it was indicated safety and feasibility of implementation of human autologous myoblasts administered at the opportunity of  coronary artery bypass grafting or by percutaneous delivery. It was further observed improvement of  the ejection fraction in patients after 3�4 month after myoblast administration. There were no noted serious side effects of the procedure of myoblast delivery which is encouraging element for start of the Phase II clinical trial.

Keywords:  myoblasts, tissue engineering, post-infarction heart.  

The Moral Controversies Concerning Stem Cell Research

Summary: On the one hand, isolation of human stem cells in laboratory conditions in 1998 opened an opportunity to elaborate a therapy for incurable diseases, yet on the other one it triggered a wave of controversy over admissibility of research on human embryos. It turned out that although it is also possible to derive stem cells from adult tissues, the research on embryo stem cells seems to be more promising. The latter type of cells can be derived from inner cell masses of a blastocyst and thus result in the destruction of the blastocyst. This kind of action involves planned destruction of the lives of embryos for the supposed therapeutic purpose. Such a procedure is unacceptable to those who are in favour of the normative status of human embryos and thus exclude their destruction. Proponents of the research in question point in turn to a vast number of  embryos that are by-products of the IVF project and will be put to destruction at any rate, even if they are not used for scientific purposes. Moreover, those who advocate this view do not see a reason why the embryo should be granted the right to life in  the way born human beings are granted it. The attempt at a compromise solution involves acceptance of research done on the already derived embryonic stem cell lines, and setting the precise date by which the destruction of embryos will have been stopped. While proponents of the research in question find it too conservative, its opponents consider it even too liberal and involving a form of cooperation in evil.

Key words: embryo, embryonic stem cells, research, moral appraisal.  

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Bone Marrow Stem Cells  – Identification and Clinical Application

Summary: Hematopoietic stem cells transplantation belongs to the routine clinical activity as a life saving procedure in several hematological malignancies and inborn errors. HSC are also a prototype of stem cells that are applicable in clinical practice. In the marrow in addition to HSC reside cells of mesenchymal origin which may differentiate into fibroblast-like cells. Our own study showed that phenotype of cells, which enrichment is associated with the number of CFU-F, is as follows: CD34-CD45-CD73⁺, CD34-CD45-CD90⁺, CD34-CD45-CD105⁺. Population of marrow cells processed for enrichment for mononuclear cells contained cells meeting the criteria of MSC. It has been already  shown that marrow cells injected into ischemic legs may bring an improvement of circulation. Our experience based on 10 treated and observed cases fully supports the notion on positive effect of marrow cell population on angiogenesis in ischemic legs. It is still open question which cells give a rise to tissue specific stem cells whether they originate from pluripotent precursors with MSC as a candidate or from tissue orientated stem cells residing in marrow.

Key words:   bone marrow stem cells, mesenchymal stem cells, CFU-F, ischemic legs.