Controversies About the Chromosomal Stability of Cultivated Mesenchymal Stem Cells: Their Clinical Use is it Safe?

The usefulness of adult stem cells in research and therapeutic applications highly relies on their genomic integrity and stability. Many laboratories including ours have addressed this concern using methods such as karyotyping, Qbanding, fluorescent in situ hybridization, array CGH, flow cytometry and Pap test to evaluate number and structure of chromosomes and cellular phenotype. This review attempts to summarize the findings reported so far for the studies on chromosomal aberrations in adult stem cells and warrant to perform certain basic tests before transplantation to avoid any adverse reactions, which will thus aid in better therapeutic output after cellular transplantation in the treatment of various diseases.     

Stem cells: are they the answer to the puzzling etiology of endometriosis?

Endometriosis is a chronic benign disease characterized by the presence of abnormally located tissue resembling the endometrium with glands and stroma. This disease has a high degree of morbidity due to chronic pelvic pain and infertility. The disease is likely to be polygenic and multifactorial, but the exact pathogenic mechanisms are still not entirely clear. Recently, adult stem cells have been identified in several tissues, including the endometrium. These cells are probably involved in the regenerative ability of the endometrial cycle, and also in the pathogenesis of proliferative gynaecological diseases, such as endometriosis. The identification of stem cells in animal and human tissues is very complex and the putative stem cells are supposed to be found through several assays such as clonogenicity, label-retaining cells, "side-population" cells, undifferentiation markers, and cellular differentiation. Bone marrow-derived stem cells transplanted into humans and animals have also been identified in eutopic endometrium and endometriotic implants. This review evaluates the available evidence regarding stem/progenitor cells in the human endometrium and explores the possible involvement of these cells in the etiology of endometriosis.     

Intracoronary infusion of mononuclear cells after PCI-treated myocardial infarction and arrhythmogenesis: is it safe?

To reduce long-term morbidity after revascularised acute myocardial infarction, different therapeutic strategies have been investigated. Cell therapy with mononuclear cells from bone marrow (BMMC) or peripheral blood (PBMC) has been proposed to attenuate the adverse processes of remodelling and subsequent heart failure. Previous trials have suggested that cell therapy may facilitate arrhythmogenesis. In the present substudy of the HEBE cell therapy trial, we investigated whether intracoronary cell therapy alters the prevalence of ventricular arrhythmias after 1 month or the rate of severe arrhythmogenic events (SAE) in the first year. In 164 patients of the trial we measured function and infarct size with cardiovascular magnetic resonance (CMR) imaging. Holter registration was performed after 1 month from which the number of triplets (3 successive PVCs) and ventricular tachycardias (VT, ≥4 successive PVCs) was assessed. Thirty-three patients (20%) showed triplets and/or VTs, with similar distribution amongst the groups (triplets: control n = 8 vs. BMMC n = 9, p = 1.00; vs. PBMC n = 10, p = 0.67. VT: control n = 9 vs. BMMC n = 9, p = 0.80; vs. PBMC n = 11, p = 0.69). SAE occurred in 2 patients in the PBMC group and 1 patient in the control group. In conclusion, intracoronary cell therapy is not associated with an increase in ventricular arrhythmias or SAE.     

Stem cells: From embryology to cellular therapy? An appraisal of the present state of art

Abtract A series of publications has dealt in the last years with topics as the isolation, properties and applications of animal stem cells (Weissman 2000. Cell 100: 157–168; Weissman 2002. N. Engl. J. Med. 346: 1567–1579; Lovell-Badge 2001. Nature 414: 88–91; Marshak et al. 2001. Stem Cell Biology. Cold Spring Harbor Laboratory Press, New york; Eridani 2002. J. Roy. Soc. Med. 95: 5–8; Borge and Evers 2003. Cytotechnology 41: 59–68; Sgaramella 2003. Cytotechnology 41: 69–73), however, the bonanza of experimental data recently accumulating have raised such an amount of controversial views and discussions that time perhaps has come for a reassessment of the basic facts in this peculiar area of research and an evaluation of possible, not unrealistic, implications.     

Mesenchymal stem cells as the game-changing tools in the treatment of various organs disorders: Mirage or reality?

Recently a growing attention in scientific community has been gathered on potential application of mesenchymal stem cells (MSCs) in various fields of medicine. Owing to the fact that they can be easily isolated from different sources, and simply proliferated in large quantities while keeping their original biological characteristics, they can be successfully used as cell-based therapeutics. Engineering MSCs and other type of stem cells to be carriers of therapeutic agents is a new tactic in the targeted gene and cell therapy of cancers and degenerative diseases. Various useful properties of MSCs including tropism toward tumor/injury site(s), weakly immunogenic, production of anti-inflammatory molecules, and safety against normal tissues have made them prone for regenerative medicine, targeted therapy and treating injured tissues, and immunological abnormalities. In this review, we introduce latest advances, methods, and applications of MSCs in gene therapy of various malignant organ disorders. Additionally, we will cover the problems and challenges which researchers have faced with when trying to translate their basic experimental findings in MSCs research to clinically applicable therapeutics.     

Downregulation of beta2-microglobulin in human cord blood somatic stem cells after transplantation into livers of SCID-mice: an escape mechanism of stem cells?

Adherently growing, non-hematopoietic somatic stem cells isolated from human cord blood were stained with the fluorescent dye PKH26 and transplanted into livers of SCID-mice to examine a possible cell fate transition. Already 7 days after transplantation stem cells were well integrated into the liver tissue. Human albumin that was not expressed by the stem cells before transplantation was detectable in the host's livers after injection of cord blood stem cells. Human alpha1-antitrypsin was detectable in stem cells already before transplantation and remained positive in the mouse liver. The most interesting observation in this study was the downregulation of human beta2-microglobulin (beta2M) in the stem cells after transplantation: beta2M is expressed constitutively in our cord blood stem cells. However, beta2M was no longer detectable by RT-PCR in all tissues where human albumin and alpha1-antitrypsin were expressed after stem cell transplantation. beta2M is known to participate as an integral part of the major histocompatibility complex. Absence of beta2M makes the residual heavy chain inactive as an antigen. Thus, downregulation of beta2M may represent an escape mechanism from killer-T cells and may be a molecular mechanism explaining the recently described "immunological blindness" [37] of stem cells. In contrast to the results obtained after direct injection of stem cells as a suspension, no consistent downregulation of beta2M was observed after transplantation of stem cells encapsulated in alginate beads to generate a compartment where stem cells are protected from the host's natural killer cells. No expression of human genes was observed after transplantation of human cord blood derived mononuclear cells (MNC) that were used as a negative control. In conclusion, we have shown that human cord blood somatic stem cells survive and are reprogrammed after transplantation into mouse livers, although a complete transdifferentiation to hepatocytes did not occur within 7 days, since some marker genes (GATA4 and alpha-fetoprotein) were still negative. Switching off expression of beta2M may be part of an intriguing and novel mechanism explaining why stem cells escape the host's immune system.     

Influence of lunar phases on suicide: the end of a myth? A population-based study

The hypothesis of lunar influence on suicide remains widespread, despite the fact that little scientific evidence to substantiate it. We conducted a population-based study to assess the influence of the lunar phases on suicides according to age, sex, and chosen method. The study included all suicides in Middle Franconia between 1998 and 2003. From a population-based sample of 3351 events, the files of 3054 suicides (1949 males and 1105 females) were complete for the study variables. Data were categorized by lunar phase, sex, age, and chosen method—“violent” vs. “non-violent” acts. No significant relationship was detected between the full, absent, and moon's interphases and suicide incidence. Nevertheless, there was a weak association between the absent moon and choice of a non-violent suicide method in men aged less than the median of 40.2 yrs. There was no evidence of a relationship between suicide and lunar phase. Some explanations for this phenomenon are discussed.     

Low survival after release into the wild: assessing “the burden of captivity” on Mallard physiology and behaviour

Captive-reared animals used in reinforcement programs are generally less likely to survive than wild conspecifics. Digestion efficiency and naive behaviour are two likely reasons for this pattern. The Mallard is a species with high adaptability to its environment and in which massive reinforcement programs are carried out. We studied physiological and behavioural factors potentially affecting body condition and survival of captive-reared Mallards after being released. Digestive system morphology and an index of body condition were compared among three groups: captive-reared birds remaining in a farm (control), captive-reared birds released into the wild as juveniles (released) and wild-born birds (wild). We also compared behaviour and diet of released vs. wild Mallards. Finally, we conducted a 1-year survival analysis of captive-reared birds after release in a hunting-free area. Gizzard weight was lower in control Mallards, but the size of other organs did not differ between controls and wild birds. The difference in gizzard weight between released and wild birds disappeared after some time in the wild. Diet analyses suggest that released Mallards show a greater preference than wild for anthropogenic food (waste grain, bait). Despite similar time-budgets, released Mallards never attained the body condition of wild birds. As a consequence, survival probability in released Mallards was low, especially when food provisioning was stopped and during harsh winter periods. We argue that the low survival of released Mallards likely has a physiological rather than a behavioural (foraging) origin. In any case, extremely few released birds live long enough to potentially enter the breeding population, even without hunting. In the context of massive releases presently carried out for hunting purposes, our study indicates a low likelihood for genetic introgression by captive-reared birds into the wild population.     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Brain mesenchymal stem cells:The other stem cells of the brain?

Multipotent mesenchymal stromal cells(MSC),have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation.The demonstration that MSCs are perivascular cells found in almost all adult tissues raises fascinating perspectives on their role in tissue maintenance and repair.However,some controversies about the physiological role of the perivascular MSCs residing outside the bone marrow and on their therapeutic potential in regenerative medicine exist.In brain,perivascular MSCs like pericytes and adventitial cells,could constitute another stem cell population distinct to the neural stem cell pool.The demonstration of the neuronal potential of MSCs requires stringent criteria including morphological changes,the demonstration of neural biomarkers expression,electrophysiological recordings,and the absence of cell fusion.The recent finding that brain cancer stem cells can transdifferentiate into pericytes is another facet of the plasticity of these cells.It suggests that the perversion of the stem cell potential of pericytes might play an even unsuspected role in cancer formation and tumor progression.