Other articles by B. Linju Yen on PubMed

• Isolation of Multipotent Cells from Human Term Placenta Stem Cells (Dayton, Ohio). 2005  |   Pubmed ID: 15625118 Current sources of stem cells include embryonic stem cells (ESCs) and adult stem cells (ASCs). However, concerns exist with either source: ESCs, with their significant ethical considerations, tumorigenicity, and paucity of cell lines; and ASCs, which are possibly more limited in potential. Thus, the search continues for an ethically conducive, easily accessible, and high-yielding source of stem cells. We have isolated a population of multipotent cells from the human term placenta, a temporary organ with fetal contributions that is discarded postpartum. These placenta-derived multipotent cells (PDMCs) exhibit many markers common to mesenchymal stem cells--including CD105/endoglin/SH-2, SH-3, and SH-4--and they lack hematopoietic-, endothelial-, and trophoblastic-specific cell markers. In addition, PDMCs exhibit ESC surface markers of SSEA-4, TRA-1-61, and TRA-1-80. Adipogenic, osteogenic, and neurogenic differentiation were achieved after culturing under the appropriate conditions. PDMCs could provide an ethically uncontroversial and easily accessible source of multipotent cells for future experimental and clinical applications.
• Increased High Sensitivity C-reactive Protein and Neutrophil Count Are Related to Increased Standard Cardiovascular Risk Factors in Healthy Chinese Men International Journal of Cardiology. Jun, 2006  |   Pubmed ID: 16305810 Epidemiologic data regarding the role of inflammation in atherosclerosis have been based mainly on Caucasian populations. Thus, we analyzed the cross-sectional relationships of inflammatory biomarkers to cardiovascular risk factors (CVRF) and related variables in a large group of healthy Chinese men, a population with a markedly lower heart disease mortality rate compared with Western populations.
• Placenta-derived Multipotent Cells Exhibit Immunosuppressive Properties That Are Enhanced in the Presence of Interferon-gamma Stem Cells (Dayton, Ohio). Nov, 2006  |   Pubmed ID: 17071860 Several types of nonhematopoietic stem cells, including bone marrow mesenchymal stem cells (BMMSCs) and embryonic stem cells, have been shown to have immunosuppressive properties. We show that human placenta-derived multipotent cells (PDMCs), which are isolated from a source without ethical concern and harbor multilineage differentiation potential, have strong immunosuppressive properties. PDMCs suppress both mitogen-induced and allogeneic lymphocyte proliferation in both CD4 and CD8 populations. The immunosuppression seen with PDMCs was significantly stronger than that with BMMSCs. Both PDMCs and BMMSCs express indoleamine 2,3-dioxygenase, but only PDMCs are positive for intracellular human leukocyte antigen-G (HLA). Mechanistically, suppression of lymphocyte reactivity by PDMCs is not due to cell death but to decreased cell proliferation and increased numbers of regulatory T cells. Addition of neutralizing antibodies to interleukin-10 and transforming growth factor (TGF)-beta partially restored lymphocyte proliferation. Unlike BMMSCs, PDMCs treated with interferon-gamma for 3 days only very minimally upregulated HLA-DR. On the contrary, PD-L1, a cell surface marker that plays an inhibitory role in T-cell activation, was upregulated and TGF-beta expression was seen. The immunosuppressive properties of PDMCs, along with their multilineage differentiation potential, ease of accessibility, and abundant cell numbers, may render these cells as good potential sources for future therapeutic applications.
• Multilineage Differentiation and Characterization of the Human Fetal Osteoblastic 1.19 Cell Line: a Possible in Vitro Model of Human Mesenchymal Progenitors Stem Cells (Dayton, Ohio). Jan, 2007  |   Pubmed ID: 17204605 The in vitro study of human bone marrow mesenchymal stromal cells (BMMSCs) has largely depended on the use of primary cultures. Although these are excellent model systems, their scarcity, heterogeneity, and limited lifespan restrict their usefulness. This has led researchers to look for other sources of MSCs, and recently, such a population of progenitor/stem cells has been found in mesodermal tissues, including bone. We therefore hypothesized that a well-studied and commercially available clonal human osteoprogenitor cell line, the fetal osteoblastic 1.19 cell line (hFOB), may have multilineage differentiation potential. We found that undifferentiated hFOB cells possess similar cell surface markers as BMMSCs and also express the embryonic stem cell-related pluripotency gene, Oct-4, as well as the neural progenitor marker nestin. hFOB cells can also undergo multilineage differentiation into the mesodermal lineages of chondrogenic and adipocytic cell types in addition to its predetermined pathway, the mature osteoblast. Moreover, as with BMMSCs, under neural-inducing conditions, hFOB cells acquire a neural-like phenotype. This human cell line has been a widely used model of normal osteoblast differentiation. Our data suggest that hFOB cells may provide for researchers an easily available, homogeneous, and consistent in vitro model for study of human mesenchymal progenitor cells.
• Placenta-derived Multipotent Cells Differentiate into Neuronal and Glial Cells in Vitro Tissue Engineering. Part A. Jan, 2008  |   Pubmed ID: 18333820 Stem cells have great potential for clinical application because of their self-renewal property and ability to differentiate into many types of cells, but because there are ethical and biological limitations with current sources of stem cells, the search continues for more suitable sources of multipotent cells. We have reported previously on a population of multipotent cells isolated from the human term placenta, an ethically unproblematic and easily available source of tissue. These placenta-derived multipotent cells (PDMCs) can differentiate into lineages of mesenchymal tissues, including osteoblasts and adipocytes, as well as non-mesenchymal tissue of neuron-like cells. We further examined the ability of PDMCs to differentiate into all 3 types of neural cells--neurons, astrocytes, and oligodendrocytes--under various induction conditions, including retinoic acid (RA), 1-methyl-3-isobutylxanthine (IBMX), and co-culture with neonatal rat brain cells. PDMCs exhibited outgrowth of processes and the expression of neuron-specific molecules such as neuron-specific enolase upon induction. Co-culture with neonatal rat brain cells also induced neural differentiation. Our results indicate that PDMCs can be differentiated into neural cell types of the human nervous system upon exposure to RA, IBMX, or primary rat brain cells.
• Brief Report--human Embryonic Stem Cell-derived Mesenchymal Progenitors Possess Strong Immunosuppressive Effects Toward Natural Killer Cells As Well As T Lymphocytes Stem Cells (Dayton, Ohio). Feb, 2009  |   Pubmed ID: 18988708 The derivation of mesenchymal progenitors from human embryonic stem cells (hESCs) has recently been reported. We studied the immune characteristics of these hESC-derived mesenchymal progenitors (EMPs) and their interactions with T lymphocytes and natural killer cells (NKs), two populations of lymphocytes with important roles in transplantation immunology. EMPs express a number of bone marrow mesenchymal stromal cell (BMMSC) markers, as well as the hESC marker SSEA-4. Immunologically, EMPs do not express HLA-DR or costimulatory molecules. On the other hand, HLA-G, a nonclassic MHC I protein involved in mediating maternal-fetal tolerance, can be found on the surface of EMPs, and its expression is increased after interferon-gamma stimulation. EMPs can suppress CD4(+) or CD8(+) lymphocyte proliferation, similar to BMMSCs. However, EMPs are more resistant to NK-mediated lysis than BMMSCs and can suppress the cytotoxic effects of activated NKs, as well as downregulating the NK-activating receptors NKp30 and NKp46. With their broad immunosuppressive properties, EMPs may represent a new potential cell source for therapeutic use.
• Upregulation of SOX9 in Lung Adenocarcinoma and Its Involvement in the Regulation of Cell Growth and Tumorigenicity Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Sep, 2010  |   Pubmed ID: 20651055 SOX9 is an important transcription factor required for development and has been implicated in several types of cancer. However, SOX9 has never been linked to lung cancer to date. Here, we show that SOX9 expression is upregulated in lung adenocarcinoma and show how it is associated with cancer cell growth.
• Endogenous KLF4 Expression in Human Fetal Endothelial Cells Allows for Reprogramming to Pluripotency with Just OCT3/4 and SOX2--brief Report Arteriosclerosis, Thrombosis, and Vascular Biology. Oct, 2010  |   Pubmed ID: 20689077 The introduction of 4 transcription factors-c-MYC, OCT3/4, SOX2, and KLF4--can reprogram somatic cells back to pluripotency. However, some of the factors used are oncogenic, making therapeutic application unfeasible. Although the use of adult stem cells expressing high endogenous levels of some of these factors allows for reprogramming with fewer exogenous genes, such cells are rare and may have accumulated genetic mutations. Our goal was to reprogram human somatic cells without oncogenic factors. We found that high endogenous expression of KLF4 in human umbilical vein endothelial cells (HUVECs) allows for generation of induced pluripotent stem cells (iPSCs) with just 2 nononcogenic factors, OCT3/4 and SOX2.
• Surface Expression of HLA-G is Involved in Mediating Immunomodulatory Effects of Placenta-derived Multipotent Cells (PDMCs) Towards Natural Killer Lymphocytes Cell Transplantation. 2011  |   Pubmed ID: 21669042 Interactions between maternal natural killer lymphocytes (NKs) and fetal tissues are important in mediating maternal-fetal tolerance. We therefore investigated the interactions of NKs to placenta-derived multipotent cells (PDMCs) isolated from the term human placenta. PDMCs have similar cell surface marker expression as bone marrow mesenchymal stem cells (BMMSCs) and additionally express human embryonic stem cell markers SSEA-4 and CD-9. Differentiation into the tri-mesodermal lineages of osteoblastic, adipocytic, and chondrogenic phenotypes can be readily achieved under the appropriate conditions. We found that PDMCs are more resistant to NK-mediated lysis than the major histocompatibility complex (MHC) class-I null target cell K562, and can suppress NK secretion of interferon-γ (IFN-γ). Moreover, as third-party cells, PDMCs suppressed the cytotoxic effects of cytokine-stimulated NKs on K562. Pretreatment of PDMCs with IFN-γ, a proinflammatory cytokine, surprisingly enhanced such immunosuppressive effects. Cell-cell contact between NKs and PDMCs is required for suppressive effects, which are partially mediated by slight upregulation of the NK inhibitory receptor killer inhibitory receptor and downregulation of the activating receptor NKp30. Moreover, enhancement of PDMC suppressive effects is also mediated by IFN-γ-induced surface expression of HLA-G--an immunomodulatory nonclassical MHC class I molecule--on PDMCs, as seen by partial reversibility with HLA-G neutralizing antibodies. With its broad immunosuppressive properties, PDMCs may represent a potential cell source for therapeutic use.
• Immunomodulatory Properties of Human Adult and Fetal Multipotent Mesenchymal Stem Cells Journal of Biomedical Science. 2011  |   Pubmed ID: 21762539 In recent years, a large number of studies have contributed to our understanding of the immunomodulatory mechanisms used by multipotent mesenchymal stem cells (MSCs). Initially isolated from the bone marrow (BM), MSCs have been found in many tissues but the strong immunomodulatory properties are best studied in BM MSCs. The immunomodulatory effects of BM MSCs are wide, extending to T lymphocytes and dendritic cells, and are therapeutically useful for treatment of immune-related diseases including graft-versus-host disease as well as possibly autoimmune diseases. However, BM MSCs are very rare cells and require an invasive procedure for procurement. Recently, MSCs have also been found in fetal-stage embryo-proper and extra-embryonic tissues, and these human fetal MSCs (F-MSCs) have a higher proliferative profile, and are capable of multilineage differentiation as well as exert strong immunomodulatory effects. As such, these F-MSCs can be viewed as alternative sources of MSCs. We review here the current understanding of the mechanisms behind the immunomodulatory properties of BM MSCs and F-MSCs. An increase in our understanding of MSC suppressor mechanisms will offer insights for prevalent clinical use of these versatile adult stem cells in the near future.
• Current Applications of Human Pluripotent Stem Cells: Possibilities and Challenges Cell Transplantation. 2012  |   Pubmed ID: 22449556 Stem cells are self-renewable cells with the differentiation capacity to develop into somatic cells with biological functions. This ability to sustain a renewable source of multi- and/or pluripotential differentiation has brought new hope to the field of regenerative medicine in terms of cell therapy and tissue engineering. Moreover, stem cells are invaluable tools as in vitro models for studying diverse fields, from basic scientific questions such as developmental processes and lineage commitment, to practical application including drug screening and testing. The stem cells with widest differentiation potential are pluripotent stem cells (PSCs), which are rare cells with the ability to generate somatic cells from all three germ layers. PSCs are considered the most optimal choice for therapeutic potential of stem cells, bringing new impetus to the field of regenerative medicine. In this article, we discuss the therapeutic potential of human PSCs (hPSCs) including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), reviewing the current preclinical and clinical data using these stem cells. We describe the classification of different sources of hPSCs, ongoing research, and currently encountered clinical obstacles of these novel and versatile human stem cells.
• 14-3-3σ Regulates β-catenin-mediated Mouse Embryonic Stem Cell Proliferation by Sequestering GSK-3β PloS One. 2012  |   Pubmed ID: 22768254 Pluripotent embryonic stem cells are considered to be an unlimited cell source for tissue regeneration and cell-based therapy. Investigating the molecular mechanism underlying the regulation of embryonic stem cell expansion is thus important. 14-3-3 proteins are implicated in controlling cell division, signaling transduction and survival by interacting with various regulatory proteins. However, the function of 14-3-3 in embryonic stem cell proliferation remains unclear.
• H2O2 Accumulation Mediates Differentiation Capacity Alteration, but Not Proliferative Decline, in Senescent Human Fetal Mesenchymal Stem Cells Antioxidants & Redox Signaling. May, 2013  |   Pubmed ID: 23088254 Mesenchymal stem cells (MSCs) with multilineage differentiation capacity and immunomodulatory properties are novel sources for cell therapy. However, in vitro expansion of these rare somatic stem cells leads to senescence, resulting in declines of differentiation and proliferative capacities. We therefore investigated the mechanisms mediating senescence in human fetal MSCs termed placenta-derived multipotent cells (PDMCs).
• The Role of RhoA Kinase Inhibition in Human Placenta-derived Multipotent Cells on Neural Phenotype and Cell Survival Biomaterials. Apr, 2013  |   Pubmed ID: 23410680 Current advances in stem cell biology have brought much hope for therapy of neuro-degenerative diseases. However, neural stem cells (NSCs) are rare adult stem cells, and the use of non-NSCs requires efficient and high-yielding lineage-specific differentiation prior to transplantation for efficacy. We report on the efficient differentiation of placental-derived multipotent cells (PDMCs) into a neural phenotype with use of Y-27632, a clinically compliant small molecular inhibitor of Rho kinase (ROCK) which is a major mediator of cytoskeleton dynamics. Y-27632 does not induce differentiation of PDMC toward the mesodermal lineages of adipogenesis and osteogenesis, but rather a neural-like morphology, with rapid development of cell extensions and processes within 24 h. Compared with conventional neurogenic differentiation agents, Y-27632 induces a higher percentage of neural-like cells in PDMCs without arresting proliferation or cell cycle dynamics. Y-27632-treated PDMCs express several neural lineage genes at the RNA and protein level, including nestin, MAP2, and GFAP. The effect of the ROCK inhibitor is cell-specific to PDMCs, and is mainly mediated through the ROCK2 isoform and its downstream target, myosin II. Our data suggest that ROCK inhibition and cytoskeletal rearrangement may allow for induction of a neural phenotype in PDMCs without compromising cell survival.
• Multipotent Human Mesenchymal Stromal Cells Mediate Expansion of Myeloid-derived Suppressor Cells Via Hepatocyte Growth Factor/c-met and STAT3 Stem Cell Reports. 2013  |   Pubmed ID: 24052949 Mesenchymal stromal cells (MSCs) are multilineage progenitors with immunomodulatory properties, including expansion of immunomodulatory leukocytes such as regulatory T lymphocytes (Tregs) and tolerogenic dendritic cells. We report that human MSCs can expand CD14(-)CD11b(+)CD33(+) human myeloid-derived suppressor cells (MDSCs). MSC-expanded MDSCs suppress allogeneic lymphocyte proliferation, express arginase-1 and inducible nitric oxide synthase, and increase the number of Tregs. This expansion occurs through the secretion of hepatocyte growth factor (HGF), with effects replicated by adding HGF singly and abrogated by HGF knockdown in MSCs. In wild-type mice, the liver, which secretes high levels of HGF, contains high numbers of Gr-1(+)CD11b(+) MDSCs, and injection of HGF into mice significantly increases the number of MDSCs. Expansion of MDSCs by MSC-secreted HGF involves c-Met (its receptor) and downstream phosphorylation of STAT3, a key factor in MDSC expansion. Our data further support the strong immunomodulatory nature of MSCs and demonstrate the role of HGF, a mitogenic molecule, in the expansion of MDSCs.
• Neocartilage Formation from Mesenchymal Stem Cells Grown in Type II Collagen-hyaluronan Composite Scaffolds Differentiation; Research in Biological Diversity. Nov-Dec, 2013  |   Pubmed ID: 24462469 Three-dimensional (3D) collagen type II-hyaluronan (HA) composite scaffolds (CII-HA) which mimics the extracellular environment of natural cartilage were fabricated in this study. Rheological measurements demonstrated that the incorporation of HA increased the compression modulus of the scaffolds. An initial in vitro evaluation showed that scaffolds seeded with porcine chondrocytes formed cartilaginous-like tissue after 8 weeks, and HA functioned to promote the growth of chondrocytes into scaffolds. Placenta-derived multipotent cells (PDMC) and gingival fibroblasts (GF) were seeded on tissue culture polystyrene (TCPS), CII-HA films, and small intestinal submucosa (SIS) sheets for comparing their chondrogenesis differentiation potentials with those of adipose-derived adult stem cells (ADAS) and bone marrow-derived mesenchymal stem cells (BMSC). Among different cells, PDMC showed the greatest chondrogenic differentiation potential on both CII-HA films and SIS sheets upon TGF-β3 induction, followed by GF. This was evidenced by the up-regulation of chondrogenic genes (Sox9, aggrecan, and collagen type II), which was not observed for cells grown on TCPS. This finding suggested the essential role of substrate materials in the chondrogenic differentiation of PDMC and GF. Neocartilage formation was more obvious in both PDMC and GF cells plated on CII-HA composite scaffolds vs. 8-layer SIS at 28 days in vitro. Finally, implantation of PDMC/CII-HA constructs into NOD-SCID mice confirmed the formation of tissue-engineered cartilage in vivo.
• Induction of Immunomodulatory Monocytes by Human Mesenchymal Stem Cell-derived Hepatocyte Growth Factor Through ERK1/2 Journal of Leukocyte Biology. Aug, 2014  |   Pubmed ID: 24714552 Monocytes are a population of leukocytes that terminally differentiate into macrophages and DCs. Whereas these differentiated progeny have inflammatory and resident--which are more immunomodulatory--phenotypes, less has been reported on the plasticity of monocytes themselves. We found that MSCs, a population of somatic stem cells, can rapidly induce human and murine monocytes through secretion of HGF to acquire an immunomodulatory phenotype to suppress T cell effector function. MSCs are multilineage postnatal progenitor cells with strong immunomodulatory effects toward T lymphocytes, NK lymphocytes, and DCs, but less is known regarding their interactions with monocytes. We found that CD14(+) human monocytes express c-Met, the receptor for HGF, and both depletion of HGF-treated CD14(+) monocytes and knockdown of HGF secretion in MSCs abrogate the suppression of anti-CD3/28-activated T cell proliferation. HGF-treated monocytes remain undifferentiated and can alter activated T cell cytokine expression from a Th1 toward Th2 profile. Moreover, monocytes cocultured with MSCs or treated with HGF alone can produce high levels of IL-10, a potent immunomodulatory cytokine. Injection of HGF to WT mice also results in an increase in IL-10(+)-expressing monocytes from the spleen, a known reservoir for circulating monocytes. Mechanistically, HGFs modulate IL-10 production in monocytes through the ERK1/2 pathway. Our data demonstrate further the pleomorphic nature of MSC immunomodulation, as well as highlight the important role of immunomodulatory monocytes in altering T cell effector function.
• Human Placenta-Derived Multipotent Cells (hPDMCs) Modulate Cardiac Injury: From Bench to Small & Large Animal Myocardial Ischemia Studies Cell Transplantation. Jan, 2015  |   Pubmed ID: 25621818 Cardiovascular disease is the leading cause of death globally, and stem cell therapy remains one of the most promising strategies for regeneration or repair of the damaged heart. We report that human placenta-derived multipotent cells (hPDMCs) can modulate cardiac injury in small and large animal models of myocardial ischemia (MI), and elucidate the mechanisms involved. We found that hPDMCs can undergo in vitro cardiomyogenic differentiation when co-cultured with mouse neonatal cardiomyocytes. Moreover, hPDMCs exert strong proangiogenic responses in vitro towards human endothelial cells mediated by secretion of hepatocyte growth factor, growth-regulated oncogene-a, and interleukin-8. To test the in vivo relevance of these results, small and large animal models of acute MI was induced in mice and minipigs, respectively, by permanent left anterior descending (LAD) artery ligation, followed by hPDMCs or culture medium only implantation with follow-up for up to 8 weeks. Transplantation of hPDMCs into mouse heart post-acute MI induction improved left ventricular function, with significantly enhanced vascularity in the cell-treated group. Furthermore, in minipigs post-acute MI induction, hPDMC transplantation significantly improved myocardial contractility compared to the control group (p=0.016) at 8 weeks post-injury. In addition, tissue analysis confirmed that hPDMC transplantation induced increased vascularity, cardiomyogenic differentiation, and anti-apoptotic effects. Our findings offer evidence that hPDMCs can modulate cardiac injury in both small and large animal models, possibly through proangiogenesis, cardiomyogenesis, and suppression of cardiomyocyte apoptosis. Our study offers mechanistic insights and preclinical evidence on using hPDMCs as a therapeutic strategy to treat severe cardiovascular diseases.
• Transplantation of Human Placenta-derived Multipotent Stem Cells Reduces Ischemic Brain Injury in Adult Rats Cell Transplantation. 2015  |   Pubmed ID: 25668287 After the onset of stroke, a series of progressive and degenerative reactions, including inflammation, is activated, which leads to cell death. We recently reported that human placenta-derived multipotent stem cells (hPDMCs) process potent anti-inflammatory effects. In this study, we examined the protective effect of hPDMC transplants in a rodent model of stroke. Adult male Sprague-Dawley rats were anesthetized. hPDMCs labeled with a vital dye of fluorescing microparticles, DiI, or vehicle were transplanted into three cortical areas adjacent to the right middle cerebral artery (MCA). Five minutes after grafting, the right MCA was transiently occluded for 60 min. Stroke animals receiving hPDMCs showed a significant behavioral improvement and reduction in lesion volume examined by T2-weighted images 4 days poststroke. Brain tissues were collected 1 day later. Human-specific marker HuNu immunoreactivity and DiI fluorescence were found at the hPDMC graft sites, suggesting the survival of hPDMCs in host brain. Grafting of hPDMCs suppressed IBA1 immunoreactivity and deramification of IBA1(+) cells in the perilesioned area, suggesting activation of microglia was attenuated by the transplants. Taken together, our data indicate that hPDMC transplantation reduced cortical lesions and behavioral deficits in adult stroke rats, and these cells could serve as a unique anti-inflammatory reservoir for the treatment of ischemic brain injury.
• Interleukin-25 Mediates Transcriptional Control of PD-L1 Via STAT3 in Multipotent Human Mesenchymal Stromal Cells (hMSCs) to Suppress Th17 Responses Stem Cell Reports. Sep, 2015  |   Pubmed ID: 26321145 Multipotent human mesenchymal stromal cells (hMSCs) harbor immunomodulatory properties that are therapeutically relevant. One of the most clinically important populations of leukocytes is the interleukin-17A (IL-17A)-secreting T (Th17) lymphocytes. However, mechanisms of hMSC and Th17 cell interactions are incompletely resolved. We found that, along with Th1 responses, hMSCs strongly suppressed Th17 responses and this required both IL-25--also known as IL--17E-as well as programmed death ligand-1 (PD-L1), a potent cell surface ligand for tolerance induction. Knockdown of IL-25 expression in hMSCs abrogated Th17 suppression in vitro and in vivo. However, IL-25 alone was insufficient to significantly suppress Th17 responses, which also required surface PD-L1 expression. Critically, IL-25 upregulated PD-L1 surface expression through the signaling pathways of JNK and STAT3, with STAT3 found to constitutively occupy the proximal region of the PD-L1 promoter. Our findings demonstrate the complexities of hMSC-mediated Th17 suppression, and highlight the IL-25/STAT3/PD-L1 axis as a candidate therapeutic target.