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At least 19 recordsLinked to original sources
PubMed2006

Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC.

The biological properties of stem cells are key to the success of cell therapy, for which MSC are promising candidates. Although most therapeutic applications to date have used adult bone marrow MSC, increasing evidence suggests that MSC from neonatal and mid-gestational fetal tissues are more plastic and grow faster. Fetal stem cells have been isolated earlier in development, from first-trimester blood and hemopoietic organs, raising the question of whether they are biologically closer to embryonic stem cells and thus have advantages over adult bone marrow MSC. In this study, we show that human first-trimester fetal blood, liver, and bone marrow MSC but not adult MSC express the pluripotency stem cell markers Oct-4, Nanog, Rex-1, SSEA-3, SSEA-4, Tra-1-60, and Tra-1-81. In addition, fetal MSC, irrespective of source, had longer telomeres (p < .001), had greater telomerase activity (p < .01), and expressed more human telomerase reverse transcriptase (p < .01). Fetal MSC were also more readily expandable and senesced later in culture than their adult counterparts (p < .01). Compared with adult MSC, first-trimester fetal tissues constitute a source of MSC with characteristics that appear advantageous for cell therapy.

Adult↗
PubMed2006

Cotransplanted bone marrow derived mesenchymal stem cells (MSC) enhanced engraftment of hematopoietic stem cells in a MSC-dose dependent manner in NOD/SCID mice.

Transplantation of marrow-derived mesenchymal stem cells (MSCs), expanded by culture in addition to whole bone marrow, has been shown to enhance engraftment of human hematopoietic stem cells (HSCs). Our hypothesis was that there might be an optimum ratio range that could enhance engraftment. We examined the percent donor chimerism according to the ratio of HSCs to MSCs in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. We tested a series of ratios of co-transplanted CD34(+) -selected bone marrow cells, and marrow-derived MSCs into sublethally irradiated NOD/SCID mice. In all experiments, 1x10(5) bone marrow derived human CD34(+) cells were administered to each mouse and human MSCs from different donors were infused concomitantly. We repeated the procedure three times and evaluated engraftment with flow cytometry four weeks after each transplantation. Serial ratios of HSCs to MSCs were 1:0, 1:1, 1:2 and 1:4, in the first experiment, 1:0, 1:1, 1:2, 1:4 and 1:8 in the second and 1:0, 1:1, 1:4, 1:8 and 1:16 in the third. Cotransplantation of HSCs and MSCs enhanced engraftment as the dose of MSCs increased. Our results suggest that the optimal ratio of HSCs and MSCs for cotransplantation might be in the range of 1:8-1:16; whereas, an excessive dose of MSCs might decrease engraftment efficiency.

Adult↗
PubMed2003

Induction of apoptosis by Se-MSC in U937 human leukemia cells through release of cytochrome c and activation of caspases and PKC-delta: mutual regulation between caspases and PKC-delta via a positive feedback mechanism.

Se-methylselenocysteine (Se-MSC) has been shown to possess potent chemopreventive and anti-tumor properties. However, its exact mechanism of action is still not well understood. The present study investigated the mechanism of Se-MSC on the induction of apoptosis using U937 human leukemia cells. Se-MSC induced dose- and time-dependent apoptosis of U937 cells as assessed by flow cytometry analysis, DNA fragmentation, and proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP). Se-MSC increased time- and dose-dependent cytochrome c accumulation in the cytosol, which was greatly inhibited by overexpression of Bcl-2, suggesting that the apoptotic effect by Se-MSC in U937 cells is mitochondrial-dependent. Se-MSC also induced activation of caspases, followed by proteolytic cleavage of PKC-delta. The Se-MSC-induced apoptosis required activities of caspases since pretreatment of a pan-caspase inhibitor z-VAD-fmk greatly suppressed the Se-MSC-induced apoptosis as well as proteolytic cleavage of PKC-delta, suggesting activation of caspases is critical for the Se-MSC-induced apoptosis, and caspases lie upstream of PKC-delta. The Se-MSC-induced apoptosis of U937 cells also required activity of PKC-delta because pretreatment of rottlerin, a specific PKC-delta inhibitor greatly blocked the Se-MSC-induced apoptosis as well as processing and activities of caspases, suggesting activation of PKC-delta is also important for the Se-MSC-induced apoptosis of U937 cells, and PKC-delta lies upstream of caspases. Together, our data suggest the apoptotic mechanism by Se-MSC in U937 cells may be related to cytochrome c release from the mitochondria, and mutual activation between caspases and PKC-delta via a positive feedback mechanism, which may potentiate the apoptotic action by Se-MSC in U937 cells.

Acetophenones↗
PubMed1999

MSC, a new benzoquinone-containing natural product with antimetastatic effect.

An orally applicable fermentation product of wheat germ containing 0.04% substituted benzoquinone (MSC) has been invented by Hungarian chemists under the trade name of AVEMAR. Oral administration (3 g/kg body weight) of MSC enhances blastic transformation of splenic lymphocytes in mice. The same treatment shortens the survival time of skin grafts in a co-isogenic mouse skin transplantation model, pointing to the immune-reconstructive effect of MSC. A highly significant antimetastatic effect of MSC has been observed in three metastasis models (3LL-HH, B16, HCR-25). The antimetastatic effect of MSC--besides the immune-reconstitution--may also be due to its cell adhesion inhibitory, cell proliferation inhibitory, apoptosis enhancing, and antioxidant characteristics, also observed in our in vitro experiments. It is even more noteworthy that combined treatment with MSC and one of the following antineoplastic agents (5-FU and DTIC)--both in wide use in every day clinical practice--exhibited a significantly enhanced antimetastatic effect in appropriate metastasis models (established from C38 mouse colon carcinoma and B16 mouse melanoma respectively) as compared to the effect elicited by any component of these therapeutic compositions (MSC + 5-FU and MSC + DTIC) administered alone. The results show that the fermented wheat germ extract (MSC) has more than an additive effect and synergistically enhanced the metastasis inhibitory effect of both antineoplastic agents studied till now. It is also worthy of mention that the synchronous treatment with MSC profoundly decreased the toxic side effects of the applied antineoplastic agents (decreased weight loss etc). Based on the biological effects of MSC--shown to be non-toxic by subacute toxicology studies--this product may be used as an adjuvant in the therapy of malignant neoplasia and other diseases caused by or following immune-deficiency.

Animals↗
PubMed2003

Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture.

Recent studies describe beneficial effects of bone marrow-derived mesenchymal stem cell infusion in animal models as well as in patients. However, data on the homing abilities of primary and culture-expanded MSC are lacking. In order to systematically investigate MSC homing we compared the fate of both primary and cultured MSC in a syngeneic mouse model. Twenty-four hours after transplantation of uncultured EGFP-transgenic MSC into sublethally irradiated mice, as many as 55-65% of injected CFU-F were recovered from the BM and 3.5-7% from the spleen. In the subsequent 4 weeks these donor CFU-F expanded 100-fold, which resulted in a normalization of femoral and splenic CFU-F numbers. This highly efficient homing of primary CFU-F contrasted with the defective homing of MSC following culture. Following their infusion immortalized multipotent syngeneic stromal cells were undetectable in BM, spleen, lymph nodes or thymus. Remarkably, following transplantation of primary MSC that had been cultured for only 24 h the seeding fraction in the BM was reduced to 10%, while after transplantation of 48 h cultured primary MSC no CFU-F were detected in the lymphohematopoietic organs. These data suggest that in vitro propagation of BM-derived MSC dramatically decreases their homing to BM and spleen.

Animals↗
PubMed1981

Prostaglandin-mediated enhancement of erythroid colonies by marrow stromal cells (MSC).

Marrow stromal cells (MSC) released a diffusible substance in split-phase culture that enhanced the response of erythroid colonies to erythropoietin when MSC were present in small numbers and suppressed when they were present in large numbers. Incremental concentrations of indomethacin inhibited the enhancement, but it did not suppress growth of MSC colonies. Radioimmunoassay of conditioned media demonstrated that MSC produced E-type prostaglandin (PGE) that was inhibited by non-lethal concentrations of indomethacin sufficient to suppress MSC enhancement of erythroid colonies. Finally, when increasing concentrations of PGE2 were added to cultures, erythroid colonies were enhanced at levels similar to those produced by small numbers of MSC which enhanced and suppressed at higher levels, producing a biphasic curve similar to that noted with increasing numbers of MSC in the underlayer. These data support our hypothesis that E-type prostaglandins are released by marrow stromal cells (MSC) to mediate the enhancement and suppression of erythroid colonies, in vitro.

Animals↗
PubMed2001

A major deletion in the cucumber mitochondrial genome sorts with the MSC phenotype.

The cucumber mitochondrial genome is unique because of its large size, paternal transmission, and the existence of a paternally transmitted mosaic (MSC) phenotype spontaneously appearing after independent tissue culture experiments. Transmission studies eliminated paternal imprinting as the genetic basis for the MSC phenotype. We identified a 13 kb region (JLV5-DEL) in the wild-type mitochondrial genome that was absent from three MSC lines. This deleted region was paternally transmitted with the MSC phenotype through the F3 and test-cross generations. Southern hybridizations and PCR amplifications using primers within the JLV5 region revealed that rare wild-type sorters possessed the wild-type region. MSC plants possess the wild-type region at levels (approximately 0.002) below detection by standard PCR reactions and Southern hybridizations, using genomic DNA. Sequence analysis of the wild-type contig revealed no homologies to mitochondrial genes and no open reading frames within JLV5-DEL. PCR amplifications across JLV5-DEL using MSC mtDNA revealed that the loss of this region was not a simple deletion and may be associated with a rearrangement. Because no genic regions were identified within the wild-type JLV5 region, the specific lesion conditioning the MSC phenotype may be associated with the putative rearrangement or another mutation that occurred during tissue culture or exists substoichiometrically in the parental line and is transmitted together with JLV5 within the same mitochondrion.

Contig Mapping↗
PubMed2005

Mesenchymal stem cells (MSC) as therapeutic cytoreagents for gene therapy.

We developed human mesenchymal stem cell (MSC) lines that could differentiate into various tissue cells including bone, neural cells, bone marrow (BM) stromal cells supporting the growth of hematopoietic stem cell (HSC), and so-called 'tumor stromal cells' mixing with tumor cells. We investigated the applicability of MSC as therapeutic cell transplanting reagents (cytoreagents). Telomerized human BM derived stromal cells exhibited a prolonged lifespan and supported the growth of hematopoietic clonogenic cells. The gene transfer of Indian hedgehog (Ihh) remarkably enhanced the HSC expansion supported by the human BM stromal cells. Gene-modified MSC are useful as therapeutic tools for brain tissue damage (e.g. brain infarction) and malignant brain neoplasms. MSC transplantation protected the brain tissue from acute ischemic damage in the midcerebral artery occlusion (MCAO) animal model. Brain-derived neurotrophic factor (BDNF)-gene transduction further enhanced the protective efficacy against the ischemic damage. MSC possessed excellent migratory ability and exerted inhibitory effects on the proliferation of glioma cells. Gene-modification of MSC with therapeutic cytokines clearly augmented the antitumor effect and prolonged the survival of tumor-bearing animals. Gene therapy employing MSC as a tissue-protecting and targeting cytoreagent would be a promising approach.

Animals↗
PubMed2006

[Porcine MSC-derived CLC induced by rabbit's cardiomyocytes extract did not induce immune reaction in vivo].

OBJECTIVE: To compare the in vivo immune reaction of transplanting porcine MSC-derived CLC with rabbit cardiomyocytes extracts induced differentiation or in vitro cultured porcine MSC. METHODS: After injecting the MSC-derived CLC or MSC to the original porcines, the number of CD4+, CD8+ T cells were determined by flow cytometry. The serum concentrations of IL-2, IL-4 were measured by ELISA, and the porcine spleen lymphocyte CTL cytotoxicity was determined by Cell Counting Kit-8 Assay. RESULTS: The numbers of CD4+ and CD8+ T cells, the serum concentrations of IL-2, IL-4 and spleen lymphocyte CTL cytotoxicity were all similar in porcines received MSC-derived CLC induced by rabbit's CMs extract or MSC transplantation. CONCLUSION: The porcine MSC-derived CLC induced by rabbit's CMs extract did not induce extra immune reaction when injected back to the original porcine.

Animals↗
PubMed2026

Overcoming Immunological Barriers in MSC-Derived Insulin-Producing Cells through CRISPR-Based Hypoimmunogenic Engineering and Translational Perspectives for Type 1 Diabetes.

Mesenchymal stromal cell (MSC)-derived insulin-producing cells (IPCs) represent an emerging strategy for &#x3b2;-cell replacement in type 1 diabetes mellitus (T1DM) owing to their differentiation potential, intrinsic immunomodulatory properties, and lower tumorigenic risk compared with pluripotent stem cell-derived platforms. However, accumulating evidence indicates that differentiation-associated immunogenicity, context-dependent immune recognition, and recurrent autoimmune responses may substantially limit long-term graft survival and therapeutic durability following transplantation. This review critically examines the immunological barriers associated with MSC-derived IPCs, including altered MHC expression, susceptibility to alloimmune and autoimmune-mediated rejection, and potential reactivation of autoreactive immune memory. We discuss the application of CRISPR-based hypoimmunogenic engineering strategies targeting antigen presentation pathways, NK-cell activation, and immune checkpoint modulation to generate more immune-evasive MSC-derived IPCs while preserving &#x3b2;-cell functionality. By integrating insights from T1DM immunopathogenesis, MSC biology, genome editing, and translational immunology, we propose a framework linking immune engineering with controlled differentiation, functional maturation, and long-term safety evaluation. In parallel, we comparatively position MSC-derived IPCs alongside clinically advancing iPSC-derived &#x3b2;-cell platforms to highlight their distinct translational niche, including potential advantages related to safety, immunomodulatory capacity, manufacturing accessibility, and scalability, while acknowledging the superior functional maturity and clinical progression currently demonstrated by iPSC-derived systems. Finally, we discuss key translational challenges, including genomic stability, immune-evasion durability, GMP-compliant manufacturing, and the need for rigorous functional and immunological benchmarking prior to clinical application of hypoimmunogenic MSC-derived IPC therapies in T1DM.

Humans↗
PubMed1994

Relationship of a mouse Sertoli cell line (MSC-1) to normal Sertoli cells.

Recently, a mouse Sertoli cell line (MSC-1) was established from transgenic mice carrying a fusion gene composed of human Müllerian inhibitory substance transcriptional regulatory sequences linked to the SV40 T-antigen gene. This cell line contained a morphologically heterogeneous population of cells that expressed characteristic Sertoli cell mRNAs such as transferrin, the beta-subunit for inhibin, and sulfated glycoprotein-2 (SGP-2). In this study, we compared various characteristics of MSC-1 cells to primary cultures of Sertoli cells from immature rats or adult mice. Our observations indicated that: 1) These cells were ultrastructurally similar to mouse Sertoli cells in culture; 2) MSC-1 cells expressed mRNA for androgen-binding protein (ABP) and SGP-1, but not the receptor for FSH; 3) The expression of SGP-2 mRNA and secretion of SGP-2 increased approximately 2-fold when cells were cultured at 41 degrees C, the nonpermissive temperature for the SV40 virus, while SGP-1 and transferrin mRNA levels and secretion were unaffected; 4) Proliferation of these cells was serum-dose dependent and temperature dependent and could be inhibited by incubating MSC-1 cells at 41 degrees C; 5) Proliferation was also significantly reduced after cells were incubated in the presence of dibutyryl cAMP (dbcAMP) for 6 days; 6) Fifteen subcultures produced from single MSC-1 cells displayed similar levels of mRNA expression for transferrin or SGP-1. Together these data indicate that the MSC-1 cell line is composed of a single cell type displaying numerous characteristics of Sertoli cells. This cell line may provide a unique source of tissue for studying various aspects of Sertoli cell behavior.

Androgen-Binding Protein↗
PubMed1999

Effect of MSC on the immune response of mice.

The supposed immunostimulatory actions of MSC, a new fermented wheat germ extract standardized to its benzoquinone composition (trade name: AVEMAR) were studied examining blastic transformation of peripheral blood lymphocytes of mice treated with MSC. It was found that MSC significantly increased the degree of blastic transformation caused by Concanavalin A. Using the B10LP to C57Bl skin graft system, MSC (0.03 and 3.0 g kg(-1) applied orally) acted in favour of restoring the immune function. On the other hand, 2,6-dimethoxy-p-benzoquinone (DMBQ), applied in equivalent doses (0.012 and 1.2 mg kg(-l)), did not shorten the rejection time of skin grafts. The immune restoring effect, as well as the blastic transformation enhancing potential of MSC may be exploited in various cases of decreased immune response.

Adjuvants, Immunologic↗
PubMed2005

[The effect of MSC on cytokine production by naive T cell differentiated in vitro].

OBJECTIVE: To investigate the effect of mesenchymal stem cell (MSC) on naive T cell and to explore its mechanism of immunoregulation. METHODS: After culturing for 3 passages, MSC was incubated with naive T cells differentiated from cord blood CD34(+) cells in vitro. Variance of cytokine produced by naive T cell in culture supernatant was analyzed by enzyme-linked immunoassays. RESULTS: On the 7th day of co-culture, a mild proliferation of T cells in the co-culture group was observed: (9.15 +/- 0.68) x 10(5)/well in MSCs + naive T cells group versus (4.87 +/- 1.33) x 10(5)/well in naive T cells alone group (P < 0.05). IFN-gamma production was lower in MSCs + naive T cells group than that in naive T cells alone group: (1.147 +/- 0.181) pg/ml versus (4.897 +/- 0.189) pg/ml (P < 0.05), but IL-2 production was higher in the co-culture group: (16.141 +/- 2.729) pg/ml versus (2.551 +/- 0.460) pg/ml (P < 0.05). Neither IL-4 nor IL-10 were detected. CONCLUSIONS: MSC have allogeneic effect on naive T cell, but may suppress alloreactive T lymphocyte and reduce the incidence of GVHD partly by decreased IFN-gamma production. The result may provide new clues for explaining immunoregulatory mechanism of MSC.

Bone Marrow Cells↗
PubMed1991

Formula for success: the role of the MSC officer and the U.S. Army dental care system.

The Army dental care system has seen significant improvements since the Dental Reform Bill of 1977-1978. This bill initiated changes that improved the management and the productivity of the dental care system. Among the many improvements initiated by these reforms was the addition of a Medical Service Corps (MSC) officer as the executive officer. This has been most noteworthy in the successful management of Dental Activities (DENTAC) and Area Dental Labs on Army installations. The job of DENTAC executive officer has become very prestigious and one of the best assignments an MSC officer can receive during his military career. The alliance between the Dental Corps and the MSC officer has been highly successful and rewarding to both parties. The object of this paper is threefold: (a) to review how the dental organization operated before the Reform Bill; (b) to discuss the present role of the dental Executive Officer; and (c) to provide recommendations for the future role of the MSC officer within the Dental Corps.

Dentists↗
PubMed2006

Chondrogenic differentiation of bovine bone marrow mesenchymal stem cells (MSCs) in different hydrogels: influence of collagen type II extracellular matrix on MSC chondrogenesis.

Bone marrow mesenchymal stem cells (MSCs) are candidate cells for cartilage tissue engineering. This is due to their ability to undergo chondrogenic differentiation after extensive expansion in vitro and stimulation with various biomaterials in three-dimensional (3-D) systems. Collagen type II is one of the major components of the hyaline cartilage and plays a key role in maintaining chondrocyte function. This study aimed at analyzing the MSC chondrogenic response during culture in different types of extracellular matrix (ECM) with a focus on the influence of collagen type II on MSC chondrogenesis. Bovine MSCs were cultured in monolayer as well as in alginate and collagen type I and II hydrogels, in both serum free medium and medium supplemented with transforming growth factor (TGF) beta1. Chondrogenic differentiation was detected after 3 days of culture in 3-D hydrogels, by examining the presence of glycosaminoglycan and newly synthesized collagen type II in the ECM. Differentiation was most prominent in cells cultured in collagen type II hydrogel, and it increased in a time-dependent manner. The expression levels of the of chondrocyte specific genes: sox9, collagen type II, aggrecan, and COMP were measured by quantitative "Real Time" RT-PCR, and genes distribution in the hydrogel beads were localized by in situ hybridization. All genes were upregulated by the presence of collagen, particularly type II, in the ECM. Additionally, the chondrogenic influence of TGF beta1 on MSCs cultured in collagen-incorporated ECM was analyzed. TGF beta1 and dexamethasone treatment in the presence of collagen type II provided more favorable conditions for expression of the chondrogenic phenotype. In this study, we demonstrated that collagen type II alone has the potential to induce and maintain MSC chondrogenesis, and prior interaction with TGF beta1 to enhance the differentiation.

Aggrecans↗
PubMed2007

Oct-4, Rex-1, and Gata-4 expression in human MSC increase the differentiation efficiency but not hTERT expression.

Micro-environment seems to exert an important influence on human mesenchymal stem cell (MSC) differentiation and proliferative capacity in bone marrow as well as in culture ex vivo. Oct-4, Rex-1, and TERT genes are well-known for the maintenance of pluripotentiality differentiation and the proliferative capacity of embryonic stem cells. Some previous data report expression of these embryonic factors in selected clones from bone marrow adult stem cells. Our goal was to study expression of Oct-4, Rex-1, and TERT in primary cultured human MSC according to the serum concentration. In addition, we have studied the expression of Gata-4 since this factor plays a key role in organogenesis. We hypothesized that low serum concentration with appropriate growth factors may induce an undifferentiated status with a re-expression of embryonic factors and extend differentiation capacity. Thus, using a defined culture medium, we report on the increased expression of Oct-4, Rex-1, and Gata-4 in human MSC. We have correlated this expression to an increase in differentiation efficiency towards osteogenic and adipogenic phenotypes. Our data suggest that the culture medium used permits the emergence of adult stem cells with a high differentiation capacity and expression of embryonic factors. These cells may have important implications for cell therapy.

Adipocytes↗