23. Umbilical cord blood-derived cells for tissue repair. Korbling M, Robinson S, Estrov Z, Champlin R, Shpall E. Cytotherapy. 2005;7:258-61.

This article provides a brief review of the solid organ systems targeted for cord blood-derived tissue repair, including injured liver tissue, type I diabetes, CNS disease and stroke.

Hematopoietic tissue-derived cells, including stem cells, have been shown to generate, besides lymphohematopoietic cells, cells of various solid organ tissues. The biological mechanisms of how those non-hematopoietic cells are produced are at the center of an intense debate, with multiple hypotheses being proposed including:

• Circulating stem cells are committed to differentiate into solid organ-specific tissue.
• A truly pluripotent seem cell may persist throughout life, as shown for the rare multipotent adult progenitor cell (MAPC)
• Hematopoietic tissue-derived cells undergo nuclear reprogramming when exposed to an non-hematopoietic environment (so-called "trans-differentiation")
• Hematopoietic tissue-derived cells or stem cells fuse with solid organ tissue cells.

Based on a variety of experimental data, Cord blood-derived cells may express a higher potential to differentiate into or fuse with solid organ tissue-specific cells after systemic or local injection. Experimental data to prove this hypothesis are not yet available.

24. Human umbilical cord blood cells: a new alternative for myocardial repair? Leor J, Guetta E, Chouraqui P, Guetta V, Nagler A. Cytotherapy. 2005;7:251-7.

Cell therapy for myocardial disease is a rapidly progressive field. However, present strategies of cell transplantation into the infarcted myocardium have limitations from practical points of view. One of the biggest challenges is to achieve a sufficient number of suitable cells. Umbilical cord blood (UCB), an unlimited source of stem/progenitor cells that could be used for transplantation into the injured heart, is readily available. The aim of this review is to describe the potential and prospect of UCB as a new supplier of cells for myocardial repair.

The authors cite data providing encouraging evidence that using UCB-derived cells can improve left ventricular function in the myocardial infarction model. The mechanism of the favorable function effects is unclear and might be related to improved healing and scar formation. The use of UCB stem cells to repair the infracted myocardium might be of importance for elderly people in whom the availability of autologous stem cells is limited. Improving methods for stem cell expansion, storage and induction of immune tolerance would increase the prospect of using UCB cells to treat MI patients, especially those who need it urgently.

25. Human Umbilical Cord Blood-Derived CD133+ Cells Enhance Function and Repair of the Infarcted Myocardium. Leor J, Guetta E, Feinberg MS, Galski H, Bar I, Holbova R, Miller L, Zarin P, Castel D, Barbash IM, Nagler A. Stem Cells. 2005 Oct 6; [Epub ahead of print]

The use of adult stem cells for myocardial tissue repair might be limited in elderly and sick people because their cells are depleted and exhausted. The present study was conducted to explore the potential of human umbilical cord blood (UCB) CD133+ progenitor cells for myocardial tissue repair in a model of extensive myocardial infarction (MI).

CD133+ progenitor cells were isolated from newborn UCB. Cells (1.2-2x10⁶) or saline (control) were infused intravenously at seven days after permanent coronary artery ligation in athymic nude rat. Left ventricular (LV) function was assessed before and one month after infusion by echocardiography. Tracking of human cells was performed by fluorescent in situ hybridization (FISH) for human X and Y chromosomes or immunostaining for HLA-DR or HLA-ABC.

One month after delivery, LV fractional shortening improved by 42+/-17% in cell-treated hearts and decreased by 39+/-10% in controls (p=0.001). Anterior wall thickness decreased significantly in controls but not in treated hearts. Microscopic examination revealed that the UCB cells were able to migrate, colonize and survive in the infarcted myocardium. Human cells were identified near vessel walls, LV cavity and were occasionally incorporated into endothelial cells in six of nine cell-treated animals but not in controls. Scar tissue from cell-treated animals was significantly populated with autologous myofibroblasts as indicated by colocalization of HLA-DR and alpha-smooth muscle actin staining.

The authors concluded that these data suggest that after MI, intravenous delivery of human UCB-derived CD 133+ cells can produce functional recovery by preventing scar thinning and LV systolic dilatation.

26. Stem cell biology and the plasticity polemic. Quesenberry PJ, Dooner G, Colvin G, Abedi M. Exp Hematol. 2005;33:389-94.

Characterization of a cord blood derived unrestricted somatic stem cell (USSC) with capacity to differentiate into hematopoietic and nonhematopoietic tissues in the absence of cell fusion has highlighted the great potential of stem cell plasticity. A great variety of stem cell types have been defined and even the most pure marrow stem cells are highly heterogeneous. Data suggest that stem cells may exist in a continuum with continually and reversibly changing phenotype. These cells also possess a capacity to produce lung, liver, skin, and skeletal muscle under conditions of tissue injury. Arguments raised against the significance of adult marrow to nonmarrow conversions including the importance of cell fusion appear fallacious. The authors conclude that we are at the beginning of an exciting and burgeoning field of research with great clinical potential.

27. Plasticity and therapeutic potential of mesenchymal stem cells in the nervous system. Phinney DG, Isakova I. Curr Pharm Des. 2005;11:1255-65.

Mesenchymal stem cells resident in adult bone marrow are best characterized by their capacity to differentiate into connective tissue cell types such as adipocytes, chondrocytes, osteoblasts and hematopoiesis-supporting stroma. Accordingly, these cells are being evaluated in human clinical trials for efficacy in treating genetic diseases of bone, to speed hematopoietic recovery after bone marrow transplantation and reduce the severity of graft versus host disease. In the past few years MSCs have also been reported to exhibit a broad degree of plasticity commensurate with other adult stem cell populations, including the ability to differentiate in vitro and in vivo into non-mesodermal cell types such as neurons and astrocytes. MSCs have also been reported to promote repair and regeneration of nervous tissue within the central and peripheral nervous system, although the mechanism by which this occurs remains indeterminate. This publication reviews evidence purporting the differentiation of MSCs into neural cell lineages and evaluates the utility of MSCs as cellular vectors for treating neurological disorders and spinal cord injury. The authors also theorize how the varied functions of MSCs and their progeny in bone marrow may extrapolate to a therapeutic benefit in models of neurological disease.

28. The fetal sheep: a unique model system for assessing the full differentiative potential of human stem cells. Porada GA, Porada C, Zanjani ED. Yonsei Med J. 2004;45 Suppl:7-14.

The authors hypothesized that the ideal way to evaluate the full plasticity of human stem cells would be to transplant them into fetal recipients at a point in development when all the organs had begun to differentiate. The transplanted cells should thus be provided with the opportunity to find the right stimulus in each organ to give rise to different cells, assuming of course, that the transplanted cells harbor that potential.

In a large animal of human hematopoietic cell plasticity in sheep, the authors have demonstrated successful engraftment and multilineage differentiation of human hematopoietic stem cells in primary, secondary and tertiary recipients. Further, they have also shown that enriched populations of human adult bone marrow and umbilical cord hematopoietic stem cells have the ability to generate functional human hepatocytes within the developing liver. The levels of human hepatocyte-like cells appeared to correlate well with the levels of human hematopoietic cell engraftment.

These data suggest that the versatility of pre-immune fetal sheep may be useful in the generation of patient-specific cells, tissues, and organs for purposes of transplantation.

29. Stem cell plasticity. Lakshmipathy U, Verfaillie C. Blood Rev. 2005;19:29-38.

The central dogma in stem cell biology has been that cells isolated from a particular tissue can renew and differentiate into lineages of the tissue it resides in. Several studies have challenged this idea by demonstrating that tissue specific cell have considerable plasticity and can cross-lineage restriction boundary and give rise to cell types of other lineages. However, the lack of a clear definition for plasticity has led to confusion with several reports failing to demonstrate that a single cell can indeed differentiate into multiple lineages at significant levels. Further, differences between results obtained in different laboratories have cast doubt on some results and several studies still await independent confirmation. In this review, the authors critically evaluate studies that report stem cell plasticity using three rigid criteria to define stem cell plasticity; differentiation of a single cell into multiple cell lineages, functionality of differentiated cells in vitro and in vivo, robust and persistent engraft of transplanted cells.

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