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Biomedical subjects

H Sariola

Publications and source records attributed to H Sariola.

At least 19 recordsLinked to original sources
PubMed2006

E6/E7 oncogenes increase and tumor suppressors decrease the proportion of self-renewing neural progenitor cells.

Many if not most tissues need a controlled number of stem cells to maintain normal function. Cancer can be seen as a process of disturbed tissue homeostasis, in which too many cells have or acquire too primitive identity. Here we measured how oncogenes and tumour suppressors affect the differentiation capacity, proportion and characteristics of progenitor cells in a model tissue. Neural progenitor cells (NPCs) were exposed to human papilloma virus E6, E7 or E6/E7 oncogenes, which degrade tumour suppressors p53 and pRb family members, respectively. E6/E7-expressing or p53-/- NPCs were able to differentiate, but simultaneously retained high capacity for self-renewal, proliferation, ability to remain multipotent in conditions promoting differentiation and showed delayed cell cycle exit. These functions were mediated through p53 and pRb family, and involved MEK-ERK signalling. Decreased amount of p53 increased self-renewal and proliferation, whereas pRb affected only proliferation. Our results suggest that the oncogenes increase whereas p53 and pRb family tumour suppressors decrease the number and proportion of progenitor cells. These findings provide one explanation how oncogenes and tumour suppressors control tissue homeostasis and highlight their importance in stem cell self- renewal, linked both to cancer and life-long tissue turnover.

Animals↗
PubMed2004

Dendritic cell subsets in childhood and in children with cancer: relation to age and disease prognosis.

Dendritic cells (DC) are a heterogeneous group of uniquely well-equipped bone marrow-derived antigen-presenting cells. They circulate in blood as precursor cells (preDC). In humans, two blood-borne subtypes of preDC can be distinguished by their differential expression of CD11c (CD11c+ preDC; monocytoid DC) and CD123 (CD123+ preDC; plasmacytoid DC). We studied the incidence of monocytoid and plasmacytoid DC in peripheral blood samples from 39 children of various ages (0.4-16.8 years) by flow cytometry, and found a significant negative correlation between the number of plasmacytoid DC and age (r = 0.421, P = 0.012). Monocytoid DC counts did not change significantly with age. Similarly, we analysed DC subsets in 19 children with cancer at the time of diagnosis prior to initiation of any myelosuppressive or antiproliferative treatment and compared the results with those obtained from gender- and age-matched control children. Patients with cancer had significantly less circulating monocytoid DC than controls (medians 13.2 versus 21.4 cells/ micro l, respectively, P = 0.042) at diagnosis, whereas absolute plasmacytoid DC counts did not differ significantly between the study groups. However, clinical outcome of the children with cancer (2.9-5 years follow-up after diagnosis) correlated with plasmacytoid DC count. Children with high plasmacytoid DC counts at diagnosis (above median) survived significantly worse (6/10 deceased) than those with low counts (1/9 deceased) (P = 0.034). Thus, circulating plasmacytoid DC counts are related to age during childhood, and development of cancer is associated with low number of monocytoid DC. A low circulating plasmacytoid DC count at diagnosis was a good prognostic sign.

Adolescent↗
PubMed2002

Transplantation of germ cells from glial cell line-derived neurotrophic factor-overexpressing mice to host testes depleted of endogenous spermatogenesis by fractionated irradiation.

With a novel method of eliminating spermatogenesis in host animals, male germ cells isolated from mice with targeted overexpression of glial cell line-derived neurotrophic factor (GDNF) were transplanted to evaluate their ability to reproduce the phenotype previously found in the transgenic animals. Successful depletion of endogenous spermatogenesis was achieved using fractionated ionizing irradiation. A dose of 1.5 Gy followed by a dose of 12 Gy after 24 h reduced the percentage of tubule cross-sections displaying endogenous spermatogenesis to approximately 3% and 10% as evidenced by histologic evaluation of testes at 12 and 21 wk, respectively, after irradiation. At this dose, no apparent harmful side effects were noted in the animals. Upon transplantation, GDNF-overexpressing germ cells were found to be able to repopulate the irradiated testes and to form clusters of spermatogonia-like cells resembling those found in the overexpressing donor mice. The cluster cells in transplanted host testes expressed human GDNF, as had been shown previously for clusters in donor animals, and both were strongly positive for the tyrosine kinase receptor Ret. Thus, we devised an efficient method for depleting the seminiferous epithelium of host mice without appreciable adverse effects. In these host mice, GDNF-overexpressing cells reproduced the aberrant phenotype found in the donor transgenic mice.

Animals↗
PubMed2001

Transient disruption of spermatogenesis by deregulated expression of neurturin in testis.

Two related ligands, glial cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN), are expressed by Sertoli cells, but their cognate ligand-binding co-receptors, GDNF family receptor alpha1 and alpha2, are displayed by different germ cells suggesting different targets for the ligands. GDNF regulates cell fate decision of undifferentiated spermatogonia 'Science 287 (2000) 1489'. The role of NRTN was now approached by targeted overexpression in mouse testis. Between 3 and 5 weeks of age, transient degeneration of spermatogenic cells was observed in approximately 20% of all five transgenic lines generated. Spermatids and pachytene spermatocytes underwent segmental degeneration, if the rete testis was undilated. When it was dilated, the spermatids and spermatocytes were more generally depleted. After 5 weeks of age, spermatogenic defects were no more observed and the NRTN overexpressing mice were fertile. The data suggest that NRTN might regulate survival and differentiation of spermatocytes and spermatids, but the low penetrance indicates that either the transgene expression has not been high enough or NRTN is not as essential as GDNF for spermatogenesis.

Animals↗
PubMed2001

Promotion of seminomatous tumors by targeted overexpression of glial cell line-derived neurotrophic factor in mouse testis.

We show with transgenic mice that targeted overexpression of glial cell line-derived neurotrophic factor (GDNF) in undifferentiated spermatogonia promotes malignant testicular tumors, which express germ-cell markers. The tumors are invasive and contain aneuploid cells, but no distant metastases have been found. By several histological, molecular, and histochemical characteristics, the GDNF-induced tumors mimic classic seminomas in men, representing a useful experimental model for testicular germ-cell tumors. The data also show that a deregulated stimulation of a normal proto-oncogene by its ligand can be an initiative event in carcinogenesis.

Aneuploidy↗
PubMed2001

The neurotrophic factors in non-neuronal tissues.

Although neurotrophic factors are defined as molecules that maintain neuronal cells, they possess a range of functions outside the nervous system. For example, glial cell line-derived neurotrophic factor is essential for ureteric branching in kidney morphogenesis and for regulating the fate of stem cells during spermatogenesis. Leukemia inhibitory factor, a member of the interleukin-6 (IL-6) ciliary neurotrophic factor family, inhibits differentiation of embryonic stem cells, induces tubulogenesis in the embryonic kidney, and regulates sperm differentiation. Other IL-6 family members are important in cardiac differentiation and they have pleiotropic functions in the hematopoietic and immune systems. Although neurotrophin receptors have been found on a number of non-neuronal tissues, they represent mostly truncated receptor isoforms that are incapable of signal transduction and may have scavenger or dominant negative functions. However, several examples can be presented of essential non-neuronal functions played by neurotrophins in e.g., cardiac, hair follicle, and vascular differentiation, and the maintenance of immune cells.

Animals↗
PubMed2001

Naive CD4+ T cells can be sensitized with IL-7.

We addressed the question whether it is possible to lower the threshold for naive T cells to respond to antigens. Purified adult and cord blood derived CD4+ CD45RA+ naive T cells were incubated in the presence of various cytokines for two days ("primed T cells"), after which the cytokines were removed by extensive washing. Primed and unprimed cells were activated with solid phase-coupled anti-CD3 and soluble anti-CD28 monoclonal antibodies (MoAb). Naive T cells, primed with interleukin(IL)-7 proliferated more vigorously than unprimed cells. Primed cells required 6 h for antigenic stimulation, whereas unprimed cells required 20 h. The priming also shifted the threshold of naive T cells in order to stimulate the antigen concentration to a lower level. The addition of IL-10 almost completely abrogated the enhancing effect of IL-7 on naive T cells. Other cytokines (IL-1, IL-2, IL-6, IL-12, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha had less effect on the cell proliferation. However, priming of naive T cells with IL-7 had no impact on the proliferation to allogeneic immature or mature dendritic cells (DC). We conclude that the antigen-independent activation of naive T cells with IL-7 prior to antigen stimulation sensitizes cells, and may be of help in trying to stimulate immune responses against weak antigens. This approach, however, does not enhance proliferative responses stimulated by DC.

Adult↗
PubMed2001

Poor yield of dendritic cell precursors from untreated pediatric cancer.

We have studied the generation of dendritic cells (DC) in vitro from healthy children and children with newly diagnosed cancer. Peripheral blood derived adherent cells were harvested and cultured in the presence of granulocyte-macrophage colony-stimulating-factor (GM-CSF) and interleukin-4 (IL-4). Differentiated DC were characterized morphologically and analyzed by flow cytometry and allogenic mixed lymphocyte reaction (MLR). The numbers of adherent cells were two-fold higher in healthy children than in those with malignant tumors: 1.5 x 10(5)/ml of blood (mean) versus 0.7 x 10(5)/ml, respectively (p = 0.025). No significant differences were found in the cell survival or yield after the in vitro cultivation of adherent cells. Cytological examination of cultured cells showed that they were similar to DC in adults, being large, irregularly shaped, with several thin membrane protrusions, and bean-shaped nuclei. Differentiated DC from healthy controls expressed CD86 and HLA-DR, but did not express monocyte markers CD14 and CD64 (FcgammaRI). The phenotype of DC from cancer patients was otherwise similar, except that a substantial proportion (24-85%) continued to express CD64 (p = 0.001). DC derived both from cancer patients and controls were strong stimulators in allogeneic MLR. We conclude that functionally capable DC can be generated in vitro from blood-derived adherent cells in children, but children with untreated cancer yield lower numbers of DC than healthy children. The continued expression of CD64 on DC derived from cancer patients may indicate that adherent cells from cancer patients are more resistant to signals inducing differentiation into DC.

Adolescent↗
PubMed2000

Regulation of cell fate decision of undifferentiated spermatogonia by GDNF.

The molecular control of self-renewal and differentiation of stem cells has remained enigmatic. Transgenic loss-of-function and overexpression models now show that the dosage of glial cell line-derived neurotrophic factor (GDNF), produced by Sertoli cells, regulates cell fate decisions of undifferentiated spermatogonial cells that include the stem cells for spermatogenesis. Gene-targeted mice with one GDNF-null allele show depletion of stem cell reserves, whereas mice overexpressing GDNF show accumulation of undifferentiated spermatogonia. They are unable to respond properly to differentiation signals and undergo apoptosis upon retinoic acid treatment. Nonmetastatic testicular tumors are regularly formed in older GDNF-overexpressing mice. Thus, GDNF contributes to paracrine regulation of spermatogonial self-renewal and differentiation.

Animals↗
PubMed2000

BMP-4 affects the differentiation of metanephric mesenchyme and reveals an early anterior-posterior axis of the embryonic kidney.

Bone morphogenetic protein-4 (BMP4), a member of the transforming growth factor-beta (TGF-beta) family, regulates several developmental processes during animal development. We have now studied the effects of BMP-4 in the metanephric kidney differentiation by using organ culture technique. Human recombinant BMP-4 diminishes the number of ureteric branches and changes the branching pattern. Our data suggest that BMP-4 affects the ureteric branching indirectly via interfering with the differentiation of the nephrogenic mesenchyme. The clear positional preference of the defects to posterior mesenchyme might reflect an early anterior-posterior patterning of the metanephric mesenchyme. The smooth muscle alpha-actin expressing cell population around the ureteric stalk, highly expressing Bmp-4 mRNA, is also expanded in kidneys treated with BMP-4. Thus, BMP-4 may be a physiological regulator of the development of the periureteric smooth muscle layer and ureteric elongation.

Animals↗
PubMed1999

Initial differentiation of the metanephric mesenchyme is independent of WT1 and the ureteric bud.

The early development of the metanephric kidney is characterized by the induced differentiation of mesenchymal cells into a stem cell population that undergoes a mesenchymal to epithelial transformation in response to stimuli from the ureteric bud. The Wilms' tumor suppressor gene, Wt1, is required for mesenchymal cells to complete this developmental program. In the absence of WT1, a prospective metanephric mesenchyme appears, but becomes apoptotic, and outgrowth of the ureteric bud from the Wolffian duct does not occur. Therefore, the examination of Wt1 -/- embryos allows the determination of those markers of early metanephric differentiation that do not require the ureteric bud or WT1 for their expression. Here, we demonstrate that several markers, including Pax-2, Six-2, and GDNF, were present as RNAs in the metanephric mesenchyme of Wt1 -/- embryos. These findings demonstrate that the metanephric mesenchyme in mutant embryos has begun to differentiate towards the nephrogenic lineage, and that this early differentiation does not require either WT1 or the presence of the ureteric bud. To determine whether WT1 functions other than to induce expression of factors that stimulate ureteric bud outgrowth, Wt1 -/- metanephric mesenchymes were recombined with wild-type ureteric buds in organ culture, but this failed to rescue tubulogenesis. However, the Wolffian duct from Wt1 -/- embryos was a competent inducer of wild-type metanephric mesenchyme.

Animals↗
PubMed1999

Bioabsorbable self-reinforced poly-L-lactide, metallic, and silicone stents in the management of experimental tracheal stenosis.

The aim of the present study was to compare, in rabbits, the biocompatibility and suitability of a bioabsorbable spiral stent made of self-reinforced poly-L-lactide (SR-PLLA) in the management of experimental tracheal stenosis with stents made of metal and silicone. Tracheobronchial stenosis, and its management, is still problematic because stenoses are not always amenable to surgical resection and reconstruction, especially concerning anastomotic problems and stenosis after lung transplantation. Stenosis can be handled with stenting, although the ideal stent has yet to be developed; all the stents available have their disadvantages. Because stenting of the airways can be only temporary, stents made of bioabsorbable materials, theoretically, offer benefits. Tracheal stenosis was created in rabbits by the extramucosal resection of cartilaginous arches of the cervical trachea. After a few weeks, the animals were operated on again, and those stenoses that had developed were dilated with a balloon. Stents then were implanted in the area of stenosis to keep the dilated trachea open. All the animals in the group with silicone stents had to be killed because of respiratory difficulties: their stents had a tendency to occlude because of internal encrustation, and they developed a hyperplastic polyp at the ends of the stents. The SR-PLLA and metallic stents were tolerated well, and after follow-up ended the animals were put to death. This experimental study showed that silicone stents had a tendency to occlude and that stents made of metal and of SR-PLLA were well tolerated and can be used in the management of airway stenosis.

Absorption↗
PubMed1999

GDNF and its receptors in the regulation of the ureteric branching.

Recent transgenic and organ culture experiments have inevitably shown that glial cell line-derived neurotrophic factor (GDNF) is a mesenchyme-derived signal for ureteric budding and branching. The signalling receptor complex for GDNF includes a dimer of Ret receptor tyrosine kinase and two molecules of GDNF family receptor alpha1. Alpha-receptors are not only needed for the ligand binding and Ret activation, but they might mediate signals without Ret. While GDNF is clearly required for ureteric branching, tissue recombination studies have shown that it is not sufficient for the completion of ureteric morphogenesis, and other signalling molecules are needed. Different experimental models have resulted in somewhat contradictory results on their molecular identity, but transforming growth factor-beta1, -beta2, fibroblast growth factor-7 and hepatocyte growth factor form, obviously among others, a redundant set of growth factors in ureteric differentiation. Three other members of the GDNF family, neurturin, artemin and persephin, are also expressed in the developing kidney, and at least neurturin and persephin promote ureteric branching in vitro, but their true in vivo roles are still unclear.

Animals↗