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PubMed2001

Direct neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism.

Little is known about how neural stem cells are formed initially during development. We investigated whether a default mechanism of neural specification could regulate acquisition of neural stem cell identity directly from embryonic stem (ES) cells. ES cells cultured in defined, low-density conditions readily acquire a neural identity. We characterize a novel primitive neural stem cell as a component of neural lineage specification that is negatively regulated by TGFbeta-related signaling. Primitive neural stem cells have distinct growth factor requirements, express neural precursor markers, generate neurons and glia in vitro, and have neural and non-neural lineage potential in vivo. These results are consistent with a default mechanism for neural fate specification and support a model whereby definitive neural stem cell formation is preceded by a primitive neural stem cell stage during neural lineage commitment.

Animals↗
PubMed2004

Are genetic determinants of asymmetric stem cell division active in hematopoietic stem cells?

Stem cells have acquired a golden glow in the past few years as they represent possible tools for reversing the damage wreak on organs. These cells are found not only in major regenerative tissues, such as the epithelia, blood and testes, but also in 'static tissues', such as the nervous system and liver, where they play a central role in tissue growth and maintenance. The mechanism by which stem cells maintain populations of highly differentiated, short-lived cells seems to involve a critical balance between alternate fates: daughter cells either maintain stem cell identity or initiate differentiation. Recent studies in lower organisms have unveiled the regulatory mechanisms of asymmetric stem cell divisions. In these models, the surrounding environment likely provides key instructive signals for the cells to choose one fate over another. Our understanding now extends to the intrinsic mechanisms of cell polarity that influence asymmetrical stem cell divisions. This article focuses on the genetic determinants of asymmetric stem cell divisions in lower organisms as a model for studying the process of self-renewal of mammalian hematopoietic stem cells.

Animals↗
PubMed2006

Embryonic cortical neural stem cells migrate ventrally and persist as postnatal striatal stem cells.

Embryonic cortical neural stem cells apparently have a transient existence, as they do not persist in the adult cortex. We sought to determine the fate of embryonic cortical stem cells by following Emx1(IREScre); LacZ/EGFP double-transgenic murine cells from midgestation into adulthood. Lineage tracing in combination with direct cell labeling and time-lapse video microscopy demonstrated that Emx1-lineage embryonic cortical stem cells migrate ventrally into the striatal germinal zone (GZ) perinatally and intermingle with striatal stem cells. Upon integration into the striatal GZ, cortical stem cells down-regulate Emx1 and up-regulate Dlx2, which is a homeobox gene characteristic of the developing striatum and striatal neural stem cells. This demonstrates the existence of a novel dorsal-to-ventral migration of neural stem cells in the perinatal forebrain.

Animals↗
PubMed1997

Intrinsic and extrinsic control of hemopoietic stem cell numbers: mapping of a stem cell gene.

We evaluated in vivo interactions between extrinsic (growth factor induced) and intrinsic (genetically determined) effectors of mouse primitive hemopoietic stem cell proliferation and numbers. Accordingly, stem cell frequency and cell cycle kinetics were assessed in eight strains of inbred mice using the cobblestone area-forming cell (CAFC) assay. A strong inverse correlation was observed between mouse lifespan and the number of autonomously cycling progenitors (CAFC day 7) in the femur. The population size of primitive stem cells (CAFC day 35) varied widely (up to sevenfold) among strains, unlike total CAFC day 7 numbers (cycling and quiescent), which were similar. Administration of the early acting cytokine flt-3 ligand to these strains resulted in activation of quiescent primitive stem cells exclusively in strains with high endogenous stem cell numbers (DBA and AKR), but was unrelated to strain-specific progenitor cell cycling. To map loci affecting stem cell frequency, we quantified stem cells in BXD recombinant inbred mice (offspring of C57BL/6 and DBA/2). The resulting strain distribution pattern showed high concordance with a marker that mapped to chromosome 18 (19 cM). Linkage with this genomic interval was associated with a likelihood of odds score of 3.3, surpassing the level required for significance. Interestingly, this segment, containing the EGR-1 gene, shows synteny with human chromosome 5q, a region strongly associated with various hematological malignancies. Our findings indicate that a gene mapping to this region is mutated in either C57BL/6 or DBA/2 (and possibly AKR) mice. These studies in apparently healthy mice may facilitate the identification of a gene implicated in human 5q-syndromes.

Animals↗
PubMed2004

Selective pressure for a decreased rate of asymmetrical divisions within stem cell niches may contribute to age-related alterations in stem cell function.

Most mammalian continuously renewing tissues are maintained by stem cells located within stem cell niches. Each niche contains a number of stem cells that replicate asymmetrically to give differentiated cells and also undergo periodic deletion and compensatory replacement by symmetrical "self-renewal" divisions of stem cells remaining within the niche. It has been recognized that there is selective pressure for an increased rate of self-renewal divisions and that the increasingly likely consequence is neoplasia. However, to date it has not been appreciated that there is also an independent selective pressure for a decreased rate of asymmetrical divisions. In this article, the origin of this second type of selective pressure is explained and its consequences explored through the use of computer modeling. It is shown that age-related changes in a range of mammalian stem cell compartments can be understood in the context of a decreased rate of asymmetrical stem cell divisions with an increased propensity for self-renewal divisions. It is proposed that a decreased rate of asymmetrical divisions impairs the ability of old stem cell compartments to respond effectively to stress.

Aging↗
PubMed2006

Expression of endoderm stem cell markers: evidence for the presence of adult stem cells in human thyroid glands.

OBJECTIVE: Adult stem cells have been detected in several human tissues. The object of this study was to investigate whether they also occur in the human thyroid gland. DESIGN: The expression of the stem cell marker Oct- 4 and the early endodermal markers GATA-4 and HNF4alpha was analyzed in histologic slides and cultured cells derived from goiters, in the FRTL5 cell line, and the HTh74, HTC, C643, and XTC133 thyroid carcinoma cell lines. MAIN OUTCOME: Stem cell markers were detectable in all primary cultures whereas in the differentiated FRTL5 cell line no expression was observed. Expression of stem cell marker mRNA was not affected by thyrotropin (TSH) stimulation and did not decrease when cells underwent several passages. Immunostaining of cultured cells and of histologic slides of goitrous tissues showed only single cells that were immunoreactive for Oct-4, GATA-4, and HNF4a. Expression of Oct-4 but not of endodermal marker GATA-4 was also detectable in some thyroid carcinoma cell lines. Fluorescence-activated cell sorter (FACS) analysis demonstrated cell populations that were positive for either Oct-4, GATA-4, or HNF4alpha but negative for thyroglobulin. When these putative, FACS-sorted stem cell populations were further analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR), expression of all stem cell markers and of Pax8 but not of thyroglobulin mRNA was detectable. CONCLUSIONS: These data provide evidence for the presence of adult stem and precursor cells of endodermal origin in the human thyroid gland.

Animals↗
PubMed2006

A mathematical model linking tree sap flow dynamics to daily stem diameter fluctuations and radial stem growth.

To date, models for simulating sap flow dynamics in individual trees with a direct link to stem diameter variation include only the diameter fluctuation driven by a change in stem water storage. This paper reports results obtained with a comprehensive flow and storage model using whole-tree leaf transpiration as the only input variable. The model includes radial stem growth based on Lockhart's equation for irreversible cell expansion. It was demonstrated that including growth is essential to obtaining good simulation results. To model sap flow dynamics, capacitance of storage tissues was assumed either constant (i.e., electrical analogue approach) or variable and dependent on the water content of the respective storage tissue (i.e., hydraulic system approach). These approaches resulted in different shapes for the desorption curve used to calculate the capacitance of storage tissues. Comparison of these methods allowed detection of specific differences in model simulation of sap flow at the stem base (F(stem)) and stem diameter variation (D). Sensitivity analysis was performed to select a limited subset of identifiable parameters driving most of the variability in model predictions of F(stem) and D Both the electrical analogue and the hydraulic system approach for the flow and storage model were successfully calibrated and validated for the case of a young beech tree (Fagus sylvatica L.). Use of an objective model selection criterion revealed that the flow and storage model based on the electrical analogue approach yielded better predictions.

Calibration↗
PubMed2001

Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency.

BACKGROUND: Ocular burns cause depletion of limbal stem cells, which leads to corneal opacification and visual loss. Autologous cultured epithelial cells can restore damaged corneas, but this technology is still developing. We sought to establish a culture system that allows preservation of limbal stem cells and preparation of manageable epithelial sheets and to investigate whether such cultures can permanently restore total limbal stem cell deficiency. METHODS: We selected a homogeneous group of patients whose limbal cell deficiency was evaluated by scoring the gravity of the clinical picture and the keratin expression pattern. Stem cells, obtained from the limbus of the contralateral eye, were cultivated onto a fibrin substrate and their preservation was evaluated by clonal analysis. Fibrin cultures were grafted onto damaged corneas. RESULTS: Fibrin-cultured limbal stem cells were successful in 14 of 18 patients. Re-epithelialization occurred within the first week. Inflammation and vascularization regressed within the first 3-4 weeks. By the first month, the corneal surface was covered by a transparent, normal-looking epithelium. At 12-27 months follow-up, corneal surfaces were clinically and cytologically stable. Three patients had a penetrating keratoplasty approximately 1 year after restoration of their corneal surface. Their visual acuity improved from light perception or counting fingers to 0.8-1.0. CONCLUSIONS: Preservation of limbal stem cells in culture gives new perspectives on the treatment of ocular disorders characterized by complete limbal stem cell deficiency. The multicenter nature of this study and the handiness and ease of long-distance transportation of the fibrin-cultured epithelial sheets suggest that this technology can now be widely applied.

3T3 Cells↗
PubMed2006

Astrocytogenesis of embryonic stem-cell-derived neural stem cells: Default differentiation.

Neural stem cells differentiate from embryonic stem cells via formation of neural stem spheres under free-floating conditions in astrocyte-conditioned medium. Subsequent culture of neural stem spheres on an adhesive substrate with fibroblast growth factor-2 promotes the migration of neural stem cells onto the substrate, resulting in an increase in the number of cells. These embryonic stem cell-derived neural stem cells can be differentiated almost exclusively into astrocytes by withdrawing fibroblast growth factor-2 from the medium without any additional instructions.

Animals↗
PubMed2004

Primitive neural stem cells from the mammalian epiblast differentiate to definitive neural stem cells under the control of Notch signaling.

Basic fibroblast growth factor (FGF2)-responsive definitive neural stem cells first appear in embryonic day 8.5 (E8.5) mouse embryos, but not in earlier embryos, although neural tissue exists at E7.5. Here, we demonstrate that leukemia inhibitory factor-dependent (but not FGF2-dependent) sphere-forming cells are present in the earlier (E5.5-E7.5) mouse embryo. The resultant clonal sphere cells possess self-renewal capacity and neural multipotentiality, cardinal features of the neural stem cell. However, they also retain some nonneural properties, suggesting that they are the in vivo cells' equivalent of the primitive neural stem cells that form in vitro from embryonic stem cells. The generation of the in vivo primitive neural stem cell was independent of Notch signaling, but the activation of the Notch pathway was important for the transition from the primitive to full definitive neural stem cell properties and for the maintenance of the definitive neural stem cell state.

Animals↗
PubMed1988

Dynamic axial brain stem distortion as a mechanism in the production of brain stem hemorrhages: role of the carotid arteries.

Dynamic axial distortion of the brain stem has long been recognized as occurring in the presence of supratentorial mass lesions. Although brain stem hemorrhages occur under these circumstances, the pathophysiology of these hemorrhages is still a matter of controversy. In the present study, the role of the carotid arteries in tethering the brain stem was evaluated during dynamic axial distortion of the neuraxis of the dog. Brain stem hemorrhages occurred in 32 of 48 dogs in which the carotid arteries were left intact (67%) and in only 9 of 46 animals in which the carotid arteries were sectioned (20%). The difference between the two groups is statistically significant (chi 2 = 19.3; P less than 0.001). In this study, we can eliminate intracranial pressure as the primary cause of the lesions because a single variable is present in one series and absent in the other, whereas intracranial pressure and its duration are kept constant. It is concluded that the tethering effect of the carotid arteries is a significant factor in the production of brain stem hemorrhages in the dog by dynamic axial distortion of the brain stem. A selective review of the literature on production of brain stem lesions is provided to support these findings.

Animals↗
PubMed1991

[The role of stem cell mobilization in the scope of autologous blood stem cell transplantation].

It is widely believed that hemopoietic stem cells have to be mobilized from extravascular sites into the circulation to guarantee a sufficient and safe blood stem cell autograft. The question of using mobilized or non-mobilized stem cells for transplantation purposes addresses the quality of hemopoietic engraftment rather than its feasibility. Two aspects are of clinical relevance: 1. The increment of peripheral cell concentration per time, and 2. shortening the duration of total aplasia following myeloablation and stem cell transplantation. When comparing the various stem cell mobilization techniques the CFU-GM yield per apheresis was highest during rh GM-CSF application (250 micrograms/m2/day continuous i.v. infusion), whereas the MNC yield was not greatly affected. More severe side effects were seen during rh GM-CSF infusion: One patient experienced an axillary phlebothrombosis. In a series of 15 advanced stage Hodgkin's lymphoma patients the reconstitutive ability of the various stem cell autografts, whether chemotherapy-, cytokine-, or non-mobilized, did not vary. Particularly in acute leukemias, mobilization of hemopoietic precursor cells does not necessarily exclude a concomitant mobilization of clonogenic tumor cells, and, therefore, the probability of disease-free survival after ABSCT might be lower when using mobilized stem cells for transplant.

Blood Component Transfusion↗
PubMed1982

Surface antigens of murine hemopoietic stem cells. IV. Characteristics of antisera exhibiting cell-lineage specificity, and differentiating ability of stem cells surviving treatment with antisera against cell-lineage antigens.

Hemopoietic stem cells express cell-lineage antigens in common with platelets, thymocytes and macrophages. Further evidence for the cell-lineage antigen model is presented. Erythrocyte-absorbed antiserum against purified mouse neutrophils cross-reacts with the hemopoietic stem cell in a lineage-specific manner. Thus, most of the anti-stem cell activity is absorbed out with neutrophils but not by other non-granulocytic hemopoietic cells. Of the four antisera tested for anti-stem cell activity, antiplatelet serum showed the highest degree of cell-lineage specificity (96% of the anti-stem cell activity satisfied cell-lineage criteria). To test predictions of the cell-lineage model of hemopoietic cell differentiation concerning the differentiating potential of stem cells selected for low concentration of cell-lineage antigen, bone marrow cells were treated with antiplatelet serum at a predetermined concentration required to produce 75-85% loss of spleen colonies. Stem cells surviving this treatment showed normal ability to form megakaryocytes and platelets. The results are consistent with postulates of the cell-lineage model.

Animals↗
PubMedDate not supplied

Do G-CSF mobilized, peripheral blood-derived stem cells from healthy, HLA-identical donors really engraft more rapidly than do G-CSF primed, bone marrow-derived stem cells? No!

For more than a decade, the notion that peripheral blood-derived stem cells engraft more rapidly than bone marrow-derived stem cells after high-dose therapy has dominated our thinking. Recently, reports that granulocyte colony-stimulating factor (G-CSF) induces a proteolytic marrow microenvironment have provided mechanistic support for that belief, compelling us to review our own experience of 29 consecutive transplants with HLA-identical blood and marrow stem cells. In contrast to several reported randomized controlled trials, we found marrow stem cells engraft just as rapidly (median day 11 for granulocytes over 500/microl and median day 17 for platelets over 20,000/microl) as blood stem cells (median day 12 and median day 19, respectively) if the donor is treated with G-CSF in the same manner before marrow harvest as the donor is treated with G-CSF before leukapheresis. These observations with healthy HLA-identical donors confirm the results of our prior randomized autotransplant study. We propose the concept that the level of activation of the stem cells (induced by G-CSF) determines engraftment kinetics and not the anatomical site of derivation.

Analysis of Variance↗
PubMed2002

Peripheral blood stem cells differ from bone marrow stem cells in cell cycle status, repopulating potential, and sensitivity toward hyperthermic purging in mice mobilized with cyclophosphamide and granulocyte colony-stimulating factor.

Peripheral blood stem cells (PBSCs) are increasingly used in autologous stem cell transplantations. We investigated the mobilizing effect of a combined cyclophosphamide (CTX) and granulocyte colony-stimulating factor (G-CSF) treatment on progenitor cells (STRA) and primitive stem cells (LTRA) in normal and splenectomized CBA/H mice. This combined treatment not only resulted in mobilization but also in expansion of hematopoietic stem cell subsets. The latter phenomenon was somewhat suppressed in splenectomized animals, but in these mice an enhanced mobilization of STRA and LTRA cells into the peripheral blood was observed. Furthermore, we studied the engraftment potential of mobilized PBSCs. Mice transplanted with PBSCs engrafted significantly better compared to mice transplanted with bone marrow stem cells from control and mobilized mice. The repopulation curve was characterized by a less-deep nadir indicating that the differences occur during the initial phase after transplantation. Contamination of autologous PBSC transplants with malignant cells is noticed frequently and is the basis for urging the use of purging modalities. Here we used hyperthermia and found that the mobilized progenitor cells in peripheral blood are more resistant to hyperthermia than those in the bone marrow (i.e., a survival of 11 +/- 5% after 90 min at 43 degrees C for peripheral blood progenitors, compared to 0.5 +/- 0.4% in bone marrow of mobilized animals and 1.6 +/- 0.5% in normal animals, respectively). Hyperthermic purging does not eliminate the superior repopulating features of a PBSC graft, as is demonstrated by an increased median survival time of lethally irradiated mice transplanted with purged PBSCs. In conclusion, our data demonstrate that CTX + G-CSF-mobilized PBSCs have an enhanced engraftment potential concomitantly with a decreased cycling activity and hence a decreased hyperthermic sensitivity. These findings support the use of these mobilized PBSCs for autologous stem cell transplantation and strengthen the basis for using hyperthermia as a purging modality.

Animals↗
PubMed1995

Total hip arthroplasty cemented femoral component distal stem centralizer. Effect on stem centralization and cement mantle.

The effectiveness, benefits, and potential risks of employing a total hip arthroplasty cemented femoral component distal centralizer were evaluated. First postoperative (6-week) radiographs of 100 primary hybrid total hip arthroplasties in consecutive groups of 50 patients without and 50 patients with a femoral stem distal centralizer were retrospectively reviewed. Femoral stems with a distal centralizer were more centralized within the femoral canal (center of stem tip to center of intramedullary canal: mean, 1.1 mm with a centralizer, 3.2 mm without; P<.0001) and more neutrally aligned (mean, 0.7 degrees valgus with a centralizer, 1.3 degrees valgus without; P < .01). Femoral stems with a distal centralizer were less likely to have a cement mantle with suboptimal thickness, that is, less than 2 mm at the medial distal femoral stem (3 of 50 stems with a centralizer, 22 of 50 stems without; chi-square, P<.0001). There were no complications, adverse effects on the cement mantle, radiographic evidence of loosening, or implant failures associated with the use of a distal centralizer, with a minimum follow-up period of 2 years.

Aged↗
PubMed2003

Primary hybrid total hip arthroplasty with a roughened femoral stem: integrity of the stem-cement interface.

One hundred and two consecutive cemented femoral stems were evaluated in 92 patients at an average 9-year follow-up and a minimum 5-year follow-up (range, 5-14 years). The stem used was cobalt chromium with a collar, normalization steps, and a roughened surface (Ra 40); the stem was inserted using contemporary cementing techniques. This series demonstrated a femoral component aseptic loosening rate of 2.0% and a femoral component survivorship of 97.2 +/- 2.0% at 10 years. One of 2 failed stems was revised at 95 months for failure at the cement-bone interface. The second failed stem showed failure at the cement-bone interface with incomplete debonding radiographically at 65 months. The remaining femoral components did not demonstrate any evidence of debonding at the stem-cement interface. These results compare favorably with other series of cemented femoral stems, as well as with those with a polished surface.

Aged↗
PubMedDate not supplied

[Revision total hip arthroplasty: how do metaphyseal onset, diaphyseal fill and a three-point-stem-fixation influence the postoperative subsidence of a revision straight-stem?].

AIM: It was the purpose of this study to determine the postoperative subsidence of a cementless hip revision stem in regard to the degree of metaphyseal onset, diaphyseal fit and a three-point contact of the stem in the femur. METHODS: Data of 50 revision total hip replacements using a cementless revision straight stem (PFM-R) could be investigated. The degree of subsidence was measured on pelvic X-rays 6 and 12 months postoperatively. The degree of metaphyseal onset, diaphyseal fit and a three-point contact of the stem in the femur was determined on the immediate postoperative X-rays. RESULTS: The amount of subsidence was strongly related to the degree of metaphyseal onset. With minor onset (up to 25 % of the possible) stems subsided 9.4 (6 months), respectively, 13.2 millimeters (12 months) in average within the investigation periods. If there was a large degree of metaphyseal onset (more than 75 % of the possible) the average subsidence was only 1.6 (6 months) or 0.9 millimeters, respectively (12 months). Neither the amount of diaphyseal fit nor the presence of three-point contact of the stem in the femur influenced the subsidence significantly. Conclusion The amount of the postoperative subsidence of stems in cementless revision total hip arthroplasty is predominantly influenced by the degree of the metaphyseal onset of the prosthesis.

Adult↗