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Results for “Cellular Microenvironment”

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At least 667 records · Page 37Linked to original sources

PubMed2005

Rac2-deficient hematopoietic stem cells show defective interaction with the hematopoietic microenvironment and long-term engraftment failure.

The hematopoietic-specific Rho GTPase, Rac2, regulates a variety of cellular functions including cell shape changes, motility, integrin-dependent adhesion, and apoptosis. In the study reported here, we demonstrate that wild-type (WT) hematopoietic stem cells/progenitors (HSC/P) preferentially engraft in nonablated Rac2(-/-) bone marrow. In addition, primitive Rac2(-/-) HSC/P transplanted into lethally irradiated WT recipients showed a significant competitive defect compared with WT cells. These defects appeared to be related to HSC/P-intrinsic defective microenvironment interactions, since Rac2(-/-) cells showed less adhesion to the femur bone marrow density 1 (FBMD-1) stromal cell line, a lower frequency of cobblestone area-forming cells, and lower performance in long-term marrow cultures in vitro when compared with WT cells. In contrast, primitive Rac2(-/-) hematopoietic cells exhibited normal progenitor colony formation in semisolid medium in vitro and normal proliferation in the steady state in vivo when compared with WT cells. Taken together, these data suggest that Rac2(-/-) stem/progenitor cells exhibit abnormal interaction with the hematopoietic microenvironment, which leads to defective long-term engraftment.

Animals↗

PubMed2006

Hypercytolipidemia-induced cellular lipoapoptosis: cytostructural and endometabolic basis of progressive organo-involution following expression of diabetes (db/db) and obese (ob/ob) mutation syndromes.

Onset expression of Type 2 (NIDDM) diabetes and obesity metabolic syndromes (DOS) are characterized by premature, progressive cytoatrophy and organo-involution induced by dysregulated cellular gluco- and lipo-metabolic cascades. The consequential systemic, interstitial and intracellular hyperlipidemia disrupts normal cytointegrity and metabolic responsivity to the established hypercaloric pericellular environments. The sequential cytostructural, metabolic and endocrine disturbances associated with the development of progressive DOS-associated hypercytolipidemia compromises cellular metabolic response cascades and promotes cytochemical disturbances which culminate with nuclear lipoapoptosis and cytoatrophy. The dramatic alterations in interstitial glucose and lipid (free fatty acids/triglycerides) concentrations are recognized to influence interstitial and cytoplasmic microchemical environments, which markedly alter cellular nutrient diffusion and active trans-membrane flux rates. The progressive exacerbation of interstitial and cytoplasmic lipid imbibition has been demonstrated to be associated with DNA fragmentation by lipo-infiltration into the chromatin matrix, inducing structural disruption and physical dissolution, indexed as nuclear lipoapoptosis. Therapeutic reduction of the severity of hypercytolipidemia-induced structural and cytochemical compromise promotes the restoration of homeostatic metabolic support for normalized cytostructural indices and supportive cellular gluco- and lipo-metabolic cascades. The re-establishment of a homeostatic interstitial microenvironment moderates the severity of cytolipidemic compromise within affected cell types, reduces nuclear lipo-infiltration and DNA lipo-dissolution, resulting in the preservation of cytostructural integrity. Through the therapeutic restoration of extra- and intra-cellular microchemical environments in genetically dysregulated metabolic syndrome models, the coincident cytochemical, endocrine and metabolic disturbances associated with progressive hypercytolipidemia, resulting from the expressed systemic hypercaloric environmental and hepato-pancreatic endometabolic disturbances which characterize Type 2 (NIDDM) diabetes-obesity and metabolic (X) syndromes, may be ameliorated.

Animals↗

PubMed2006

5'-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments.

Low oxygen gradients (hypoxia and anoxia) are important determinants of pathological conditions under which the tissue blood supply is deficient or defective, such as in solid tumors. We have been investigating the relationship between the activation of hypoxia-inducible factor 1 (HIF-1), the primary transcriptional regulator of the mammalian response to hypoxia, and 5'-AMP-activated protein kinase (AMPK), another regulatory system important for controlling cellular energy metabolism. In the present study, we used mouse embryo fibroblasts nullizygous for HIF-1alpha or AMPK expression to show that AMPK is rapidly activated in vitro by both physiological and pathophysiological low-oxygen conditions, independently of HIF-1 activity. These findings imply that HIF-1 and AMPK are components of a concerted cellular response to maintain energy homeostasis in low-oxygen or ischemic-tissue microenvironments. Finally, we used transformed derivatives of wild-type and HIF-1alpha- or AMPKalpha-null mouse embryo fibroblasts to determine whether AMPK is activated in vivo. We obtained evidence that AMPK is activated in authentic hypoxic tumor microenvironments and that this activity overlaps with regions of hypoxia detected by a chemical probe. We also showed that AMPK is important for the growth of this tumor model.

AMP-Activated Protein Kinases↗

PubMed2002

In vivo evaluation of cellular and acellular bovine pericardia fixed with a naturally occurring crosslinking agent (genipin).

A cell extraction process was employed in the study to remove the cellular components from bovine pericardium, leaving a framework of largely insoluble collagen and elastin. It was hypothesized in the literature that this process may decrease the antigenic load (or increase the biocompatibility) within the material. Additionally, acellular tissues may provide a natural microenvironment for host-cell migration to regenerate the tissue. The study was to evaluate the biocompatibility of cellular and acellular bovine pericardia fixed with a naturally occurring crosslinking agent (genipin) implanted subcutaneously in a growing rat model. Additionally, the tissue regeneration rate in the genipin-fixed acellular tissue was investigated. The glutaraldehyde-fixed counterparts were used as controls. The results indicated that the degrees in inflammatory reaction for the genipin-fixed cellular and acellular tissues were significantly less than their glutaraldehyde-fixed counterparts. Additionally, it was noted that the inflammatory reactions for the glutaraldehyde-fixed cellular and acellular tissues lasted much longer than their genipin-fixed counterparts. The tissue regeneration rate for the genipin-fixed acellular tissue was significantly faster than its glutaraldehyde-fixed counterpart. The calcium content of each studied group, analyzed by atomic absorption. did not change significantly until at the 52nd week, postoperatively. The differences in calcium content between the cellular and acellular tissues were insignificant for both the glutaraldehyde- and genipin-fixed groups throughout the entire course of the study. In summary, the biocompatibility of the genipin-fixed cellular and acellular tissues was superior to their glutaraldehyde-fixed counterparts. The genipin-fixed acellular tissue provided a better microenvironment for tissue regeneration than its glutaraldehyde-fixed counterpart, due to its low cytotoxicity. These results suggested that the genipin-fixed acellular tissue might be used as a tissue-engineering matrix in the clinical applications.

Animals↗

PubMed1979

The pathology of vitreous hemorrhage. II. Ultrastructure.

We undertook an ultrastructural study of the dual processes of hemolysis and vitreous membrane formation during the resolution of vitreous blood clots in rabbits. Red blood cell degradation began within 24 hours before the onset of the inflammatory response and occurred mainly in the extracellular matrix. Macrophage activity was directed at clearing lysed RBC debris, rather than engulfing whole RBCs. Hemolysis in the vitreous may have been initiated by the unfavorable microenvironment. Two types of vitreous membranes occurred during vitreous clot lysis. Cellular membranes were composed of aggregates of giant macrophages enclosed within a thin collagen sheet. Acellular membranes developed from coaggregated vitreous collagen fibers. A prominent acellular membrane surrounded the blood clot as a pseudocapsule. No fibroblasts or fresh collagen deposition were observed.

Animals↗

PubMed2001

A novel system for investigating the ability of smooth muscle cells and fibroblasts to regulate adhesion of flowing leukocytes to endothelial cells.

Stromal cells may contribute to the inflammatory processes which lead to the recruitment of circulating leukocytes. Here, we describe a multicellular model in which chosen cellular elements of tissue can be cocultured with endothelial cells (EC). Cocultures can be incorporated into a novel parallel plate flow chamber to determine if stromal cells influence the patterns of leukocyte adhesion to the EC. As an example relevant to the pathology of atherosclerosis, EC were cultured with arterial smooth muscle cells (SMC) of the 'secretory' phenotype. EC and secretory SMC were cultured on the opposite faces of commercially available porous polyethylene terepthalate (PET) culture inserts, which fitted into a parallel plate flow chamber. Binding of flowing purified lymphocytes, labelled with the fluorochrome calcein-AM, to cocultured EC was assessed by fluorescence microscopy. Lymphocyte adhesion was negligible on unstimulated EC cultured alone or cocultured with SMC. However, when tumour necrosis factor-alpha (TNF) was added to cocultures, the EC supported greatly increased levels of lymphocyte adhesion compared to TNF-treated EC cultured alone. Additionally, cocultured EC responded to TNF at concentrations far below those at which EC cultured alone responded. This priming was specific in that skin fibroblasts cocultured with EC did not modify lymphocyte adhesion induced by TNF. Thus, we have developed a coculture model to determine the ability of tissue stromal cells to modify leukocyte recruitment. This may have wide applications in the study of the cellular pathology of inflammation by allowing the contribution of the local microenvironment to be assessed.

Arteriosclerosis↗

PubMed2001

The biofilm matrix--an immobilized but dynamic microbial environment.

The biofilm matrix is a dynamic environment in which the component microbial cells appear to reach homeostasis and are optimally organized to make use of all available nutrients. The major matrix components are microbial cells, polysaccharides and water, together with excreted cellular products. The matrix therefore shows great microheterogeneity, within which numerous microenvironments can exist. Although exopolysaccharides provide the matrix framework, a wide range of enzyme activities can be found within the biofilm, some of which will greatly affect structural integrity and stability.

Bacterial Physiological Phenomena↗

PubMed2004

Molecular mechanisms behind the dose-dependent differential activation of MAPK pathways induced by transforming growth factor-beta1 in hematopoietic cells.

Transforming growth factor-beta (TGF-beta) controls a wide range of cellular responses, including cell proliferation, lineage determination, differentiation, and apoptosis, and figures prominently in animal development. It is considered as a pleiotropic factor because it can exert a positive or negative effect on various cellular processes depending on developmental stage of the target cell, its microenvironment, and also its biochemical make up. It has been shown to have a strong inhibitory effect on hematopoietic stem cell proliferation and differentiation. We have earlier shown that TGF-beta1 exerts a bidirectional effect on hematopoietic cell proliferation as a function of its concentration. Although it acted as an inhibitor at high concentrations, at low concentrations it stimulated the stem/progenitor cells. We also provided evidence that the differential activation of mitogen-activated protein kinase pathways was responsible for the observed bidirectional effect. In the present study, we examined the molecular mechanism behind this phenomenon. We observed that the high inhibitory concentrations of TGF-beta1 induced a strong phosphorylation of SMAD 3 and also activated stress kinase-related transcription factors, namely c-Jun and ATF-2. On the other hand, low stimulatory concentrations acted in a SMAD 3-independent pathway and activated STAT proteins. Our results clearly show that differential activation of signal transduction pathways by TGF-beta1 as a function of its concentration underlies its bidirectional effect on hematopoietic cells.

Adaptor Proteins, Signal Transducing↗

PubMed2006

RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis.

OBJECTIVES: Receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) have been demonstrated to be critical regulators of osteoclast generation and activity. In addition, RANKL has been implicated as an important mediator of bone erosion in rheumatoid arthritis (RA). However, the expression of RANKL and OPG at sites of pannus invasion into bone has not been examined. The present study was undertaken to further elucidate the contribution of this cytokine system to osteoclastogenesis and subsequent bone erosion in RA by examining the pattern of protein expression for RANKL, OPG and the receptor activator of NF-kappaB (RANK) in RA at sites of articular bone erosion. METHODS: Tissues from 20 surgical procedures from 17 patients with RA were collected as discarded materials. Six samples contained only synovium or tenosynovium remote from bone, four samples contained pannus-bone interface with adjacent synovium and 10 samples contained both synovium remote from bone and pannus-bone interface with adjacent synovium. Immunohistochemistry was used to characterize the cellular pattern of RANKL, RANK and OPG protein expression immediately adjacent to and remote from sites of bone erosion. RESULTS: Cellular expression of RANKL protein was relatively restricted in the bone microenvironment; staining was focal and confined largely to sites of osteoclast-mediated erosion at the pannus-bone interface and at sites of subchondral bone erosion. RANK-expressing osteoclast precursor cells were also present in these sites. OPG protein expression was observed in numerous cells in synovium remote from bone but was more limited at sites of bone erosion, especially in regions associated with RANKL expression. CONCLUSIONS: The pattern of RANKL and OPG expression and the presence of RANK-expressing osteoclast precursor cells at sites of bone erosion in RA contributes to the generation of a local microenvironment that favours osteoclast differentiation and activity. These data provide further evidence implicating RANKL in the pathogenesis of arthritis-induced joint destruction.

Adolescent↗

PubMed2006

My approach to reporting a gastric biopsy.

The protracted inflammation of the gastric mucosa induces profound changes in the microenvironment of the gastric cells. These changes modify the molecular signals that orchestrate morphogenesis and cell differentiation in the stem cells of the crypts. The expression of this adjustment to the new microenvironment is evidenced by the appearance of differentiated metaplastic cells (intestinal, bronchial-ciliated, pancreatic or (pseudo) pyloric, all deriving from the same embryological origin). The inability of stem cells to readapt to the new microenvironment may lead to genomic aberrations such as the retention of cellular products (glassy cells) or to neoplastic transformation. In this report, parameters such as gastric mucosal inflammation, Helicobacter pylori, atrophy, intestinal metaplasia and/or pseudopyloric metaplasia found in gastric biopsy specimens were individually classified according to their extension in sections as grade 1 (focal distribution in sections from individual biopsy specimens) and grade 2 (present in the entire width-distance across-in sections from individual biopsy specimen). The rationale is that a biopsy grade 2 was harvested from a larger mucosal area having that particular change. Each individual parameter gives a score, and the sum of all individual scores gives the total score. The proposed system might allow monitoring the results of treatment in follow-up biopsies. Divergent clinical results in the frequency/incidence of gastritis (including body-autoimmune gastritis), of H pylori strains, of various metaplasias and neoplasias, in disparate geographical regions substantiate the conviction that these parameters are much influenced by the environment. This knowledge is crucial, considering that environmental diseases are theoretically preventable.

Animals↗

PubMed1993

Anisotropic and heterogeneous diffusion in the turtle cerebellum: implications for volume transmission.

1. Measurements of extracellular diffusion properties were made in three orthogonal axes of the molecular and granular layers of the isolated turtle cerebellum with the use of iontophoresis of tetramethylammonium (TMA+) combined with ion-selective microelectrodes. 2. Diffusion in the extracellular space of the molecular layer was anisotropic, that is, there was a different value for the tortuosity factor, lambda i, associated with each axis of that layer. The x- and y-axes lay in the plane parallel to the pial surface of this lissencephalic cerebellum with the x-axis in the direction of the parallel fibers. The z-axis was perpendicular this plane. The tortuosity values were lambda x = 1.44 +/- 0.01, lambda y = 1.95 +/- 0.02, and lambda z = 1.58 +/- 0.01 (mean +/- SE). By contrast, the granular layer was isotropic with a single tortuosity value, lambda Gr = 1.77 +/- 0.01. 3. These data confirm the applicability of appropriately extended Fickian equations to describe diffusion in anisotropic porous media, including brain tissue. 4. Heterogeneity between the molecular and granular layer was revealed by a striking difference in extracellular volume fraction, alpha, for each layer. In the molecular layer alpha = 0.31 +/- 0.01, whereas in the granular layer alpha = 0.22 +/- 0.01. 5. Volume fraction and tortuosity affected the time course and amplitude of extracellular TMA+ concentration after iontophoresis. This was modeled by the use of the average parameters determined experimentally, and the nonspherical pattern of diffusion in the molecular layer was compared with the spherical distribution in the granular layer and agarose gel by computing isoconcentration ellipsoids. 6. One functional consequence of these results was demonstrated by measuring local changes in [K+]o and [Ca2+]o after microiontophoresis of a cerebellar transmitter, glutamate. The ratios of ion shifts in the x- and y-axes in the granular layer were close to unity, with a ratio of 1.04 +/- 0.08 for the rise in [K+]o and 1.03 +/- 0.17 for the decrease in [Ca2+]o. In contrast, ion shifts in the molecular layer had an x:y ratio of 1.44 +/- 0.14 for the rise in [K+]o and 2.10 +/- 0.42 for the decrease in [Ca2+]o. 7. These data demonstrate that the structure of cellular aggregates can channel the migration of substances in the extracellular microenvironment, and this could be a mechanism for volume transmission of chemical signals. For example, the preferred diffusion direction of glutamate along the parallel fibers would help constrain an incoming excitatory stimulus to stay "on-beam."

Animals↗

PubMed2002

Tumor cell dissemination in follicular lymphoma.

The derivation of follicular lymphomas (FLs) from germinal centers is not only supported by their morphologic appearance with a nodular growth pattern and a germinal center-like cellular composition, but also by the presence of ongoing somatic hypermutation (a germinal center B cell-specific process) during their clonal expansion. The intraclonal sequence diversity of the tumor cells and their follicular growth pattern allows one to analyze lymphoma cell dissemination and the way the tumor "metastasizes" to distinct follicles. In the present study, we analyzed individual follicles of 3 FLs by micromanipulation of single cells from individual lymphoma follicles and amplification of immunoglobulin V region genes. Genealogical trees for the V(H) and the V(L) gene rearrangements were constructed to analyze the clonal relationship among individual cells of 3 distinct follicles of each case. In all 3 cases there is evidence that distinct tumor follicles are founded by many tumor cells, suggesting that there is extensive migration of the tumor cells among follicles. The observation that the tumor cells of FLs retain their follicular growth patterns despite this cellular migration supports the idea that they depend on the follicular microenvironment for their clonal expansion.

Cell Movement↗

PubMed1999

Human follicular dendritic cells inhibit superantigen-induced T-cell proliferation by distinct mechanisms.

Follicular dendritic cells (FDCs) reside within germinal centers of secondary lymphoid tissue where they play a critical role in antigen-driven immune responses. FDCs express numerous adhesion molecules that facilitate cellular interactions with B and T cells within the germinal center microenvironment. Although human FDCs have been shown to influence B-cell development, very little is known about the ability of FDCs to regulate T-cell responses. To investigate this functional aspect of FDCs, highly enriched preparations were isolated by magnetic cell separation using the FDC-restricted monoclonal antibody HJ2. We found that isolated human FDCs inhibited proliferation of both autologous and allogeneic T cells, and were dependent on the number of FDCs present. Inhibition by FDCs was observed using two serologically distinct superantigens at multiple concentrations (Staphylococcus enterotoxin A and B). In contrast, B cells failed to inhibit, and often augmented superantigen-induced T-cell proliferation. Antibody-blocking studies showed that CD54 and CD106 were involved in the ability of FDC to inhibit T-cell proliferative responses. When FDCs and T cells were separated by a semipermeable membrane, the inhibitory effect was partially abrogated, demonstrating that in addition to cell-cell interactions, a soluble factor(s) was also involved in the process. The addition of indomethicin to cultures improved the proliferative response in the presence of FDCs, indicating that inhibition was mediated, in part, by prostaglandins. These results indicate that FDCs regulate T-cell proliferation by two molecular mechanisms and that FDC:T-cell interactions may play a pivotal role in germinal center development.

Antigen Presentation↗

PubMed2003

Pathogenesis and treatment of HIV-associated renal diseases: lessons from clinical and animal studies, molecular pathologic correlations, and genetic investigations.

HIV infection is associated with several renal syndromes, including acute renal failure. Chronic renal failure directly linked to HIV infection includes thrombotic microangiopathic renal diseases, immune-mediated glomerulonephritides, and HIV-associated nephropathy. A renal biopsy may be necessary for diagnosis. The development of HIV-associated nephropathy has been definitively linked to renal cellular infection, but the disease affects only a minority of patients, typically men of African descent. Therefore, factors determining disease expression in infected patients must now be emphasized. The pathogenic mechanisms involved in HIV-associated renal disease remain obscure. Genetic factors, as well as renal cellular responses, mediated by HIV proteins (including an immune-activated microenvironment) capable of presenting antigen in susceptible hosts probably explain most cases. HIV-associated nephropathy has a characteristic pathologic phenotype, including glomerular, tubular, and interstitial changes, and ultrastructural findings. Infection of the glomerular epithelial cell, or podocyte, and consequent structural and biochemical changes may be pivotal in pathogenesis. The HIV-1 transgenic mouse is an important model for understanding disease pathogenesis, particularly the role of HIV proteins in mediating renal tissue injury. Rigorously controlled randomized trials have not evaluated treatment, but corticosteroids and angiotensin-converting enzyme inhibitors have been used. Highly active antiretroviral therapy seems to have decreased the incidence of end-stage renal disease related to HIV infection and, in case reports, to have improved renal functional and pathologic outcomes of HIV-associated nephropathy. Outcomes in patients undergoing hemodialysis and peritoneal dialysis have improved, and current research focuses on renal transplantation for treatment of HIV-infected patients.

Animals↗

PubMed1989

Delayed activation of quiescent donor hematopoietic stem cells in the host marrow cavity by anti-host monoclonal antibody.

To understand the mechanisms controlling hematopoietic engraftment in untreated, normal recipients, we investigated the fate of parental, donor hematopoietic stem cells after apparent graft failures in unconditioned F1 hybrid recipient mice. By administering an anti-host H-2K monoclonal antibody, which targets host cells but spares the donor, we found that chimerism could be induced by delayed conditioning in animals with apparent graft failure. Engraftment kinetics in the host were followed by typing individual colony forming unit--granulocyte/macrophage (CFU-GM) colonies for their origin and showed that parental cells, which were otherwise virtually absent, become promptly detectable within the marrow cavity after antibody administration. Marrow transfers to secondary hosts suggested that parental stem cells were present in the marrow of the untreated recipients. These findings establish that the elimination of all parental cells cannot account for the absence of peripheral blood chimerism in the unconditioned F1 hybrid recipient. Thus, viable and functional donor stem cells, which remain quiescent in the host marrow, can be activated by a selective conditioning regimen and can rescue an apparent graft failure. The selective activation in vivo of marked stem cells in an unirradiated microenvironment may be a useful system to study the regulation of cellular proliferation within the marrow cavity.

Animals↗

PubMed1988

X-ray and cis-diamminedichloroplatinum(II) cross-resistance in human tumor cell lines.

Clinical studies have suggested a close correlation between cis-diamminedichloroplatinum(II) (cisplatin) and radiation resistance. To determine whether this cross-resistance is due to an inherent cellular resistance to both agents, ten early passage human tumor cell lines were examined for their radiation and cisplatin sensitivity in vitro. Previous studies have suggested that these early passage tumor cell lines retain many of their in vivo characteristics and are therefore good models for tumor cells in vivo. Radioresistance was strongly associated with cisplatin resistance in these cell lines. Four of the cell lines examined were radioresistant, having Dos greater than 2.0 Gy. These four lines were also resistant to cisplatin, with the dose reducing survival to 10% greater than 1.29 microM. The remaining six cell lines had Dos ranging from 1.07 to 1.57 Gy of X-ray and doses reducing survival to 10% of less than 0.83 microM cisplatin. Because early passage human tumor cell lines were used, resistance or sensitivity to radiation and cisplatin most likely developed in vivo and was not due to selection in vitro. These results indicate that cross-resistance between cisplatin and radiation in vivo is probably due primarily to an inherent cellular resistance to these agents and not necessarily to the tumor microenvironment in situ.

Adenocarcinoma↗

PubMed1995

Tumor-bone interactions in skeletal metastasis.

Bone metastases are a frequent clinical problem in patients with breast, prostate, and other cancers. Formation of these lesions is a site-specific process determined by multiple cellular and molecular interactions between the cancer cells and the bone microenvironment. Clinical studies, and in vivo and in vitro experimental approaches, have been useful to dissect different stages of this process. Mechanisms identified as relevant to cancer spreading and tumoral growth in the bones include (a) early vascular spread of cancer cells to bones; (b) adhesion of cancer cells to the bone microvasculature and matrix components; (c) presence of growth factors and chemo-attractants in bone; (d) osteolysis by osteoclasts, tumor associated macrophages, and cancer cells; and (e) tumor-induced local osteoblastic proliferation. Although none of these mechanisms alone are responsible for the development of bone metastases, their investigation may lead to novel therapeutic approaches that specifically block these stages and, thus, may hinder development of bone metastasis. The use of bisphosphonates and other experimental strategies already is being tested in clinical trials.

Animals↗

PubMed1996

Hematopoietic supportive functions of mouse bone marrow and fetal liver microenvironment: dissection of granulocyte, B-lymphocyte, and hematopoietic progenitor support at the stroma cell clone level.

We dissected the functions of the microenvironment of bone marrow (BM) and fetal liver (FL) at the cellular level by cloning individual stromal calls and characterizing their phenotypical and functional features. Stromal cell clones derived from FL are large in size (mean forward light scatter intensity [mFSC] of 450), express the surface antigen Thy-1 but not Sca-1 and 6 out of 6 are able to differentiate into fat accumulating adipocytes. BM derived stromal cell clones are either small (mFSC of 250) or large (mFSC of 450), express Sca-1 but not Thy-1 and only 2 out of 7 differentiate towards adipocytes. Heterogeneity in terms of vascular adhesion molecule-1, intracellular adhesion molecule-1 and heat stable antigen expression was found among the different cell clones. Functional assays using long- and short-term cocultures of stromal and hematopoietic calls revealed: (1) the capacity of 8 out of 12 stromal cell clones to support the expansion of primitive hematopoietic progenitors (colony forming unit spleen day 12) more than 10 weeks. Fat accumulation but not expression of stem cell factor by stromal cells did correlate with this supportive function. (2) Better support of granulocyte maturation and proliferation by BM- compared to FL-derived stromal cell clones. However, stromal cell clones from both organs expressed macrophage-colony stimulating factor. (3) The ability of 4 out of 12 stromal cell clones (derived from both, FL and BM) to support the expansion of Interleukin-7 dependent pre-B cells from the BM. Pre-B cell growth stimulating factor was not restricted to supporters. (4) Mutual exclusiveness of myeloid and lymphoid support in that a given stromal cell clone supported either pre B-cell or granulocyte expansion. Experiments comparing the support of BM- and FL-derived hematopoietic progenitors showed identical responses of late (B220+/c-kit-) but strikingly different responses of early (B220+/c-kit+) pre-B cells, revealing different proliferation requirements for FL- versus BM- derived early pre-B cells in vitro.

Adipose Tissue↗