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Songtao Shi

Publications and source records attributed to Songtao Shi.

At least 19 recordsLinked to original sources
PubMed2007

EphB/ephrin-B interaction mediates adult stem cell attachment, spreading, and migration: implications for dental tissue repair.

Human adult dental pulp stem cells (DPSCs) reside predominantly within the perivascular niche of dental pulp and are thought to originate from migrating neural crest cells during development. The Eph family of receptor tyrosine kinases and their ligands, the ephrin molecules, play an essential role in the migration of neural crest cells during development and stem cell niche maintenance. The present study examined the expression and function of the B-subclass Eph/ephrin molecules on DPSCs. Multiple receptors were primarily identified on DPSCs within the perivascular niche, whereas ephrin-B1 and ephrin-B3 were expressed by the surrounding pulp tissue. EphB/ephrin-B bidirectional signaling inhibited cell attachment and spreading, predominately via the mitogen-activated protein kinase (MAPK) pathway for forward signaling and phosphorylation of Src family tyrosine kinases via reverse ephrin-B signaling. DPSC migration was restricted through unidirectional ephrin-B1-activated EphB forward signaling, primarily signaling through the MAPK pathway. Furthermore, we observed that ephrin-B1 was downregulated in diseased adult teeth compared with paired uninjured controls. Collectively, these studies suggest that EphB/ephrin-B molecules play a role in restricting DPSC attachment and migration to maintain DPSCs within their stem cell niche under steady-state conditions. These results may have implications for dental pulp development and regeneration.

Adult↗
PubMed2006

Mesenchymal stem cell-mediated functional tooth regeneration in swine.

Mesenchymal stem cell-mediated tissue regeneration is a promising approach for regenerative medicine for a wide range of applications. Here we report a new population of stem cells isolated from the root apical papilla of human teeth (SCAP, stem cells from apical papilla). Using a minipig model, we transplanted both human SCAP and periodontal ligament stem cells (PDLSCs) to generate a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This work integrates a stem cell-mediated tissue regeneration strategy, engineered materials for structure, and current dental crown technologies. This hybridized tissue engineering approach led to recovery of tooth strength and appearance.

Animals↗
PubMed2006

Transplantation of mesenchymal stem cells is an optimal approach for plastic surgery.

Mesenchymal stem cells (MSCs) are able to differentiate into a variety of cell types, offering promising approaches for stem cell-mediated tissue regeneration. Here, we explored the potential of utilizing MSCs to reconstruct orofacial tissue, thereby altering the orofacial appearance. We demonstrated that bone marrow MSCs were capable of generating bone structures and bone-associated marrow elements on the surfaces of the orofacial bone. This resulted in significant recontouring of the facial appearance in mouse and swine. Notably, the newly formed bone and associated marrow tissues integrated with the surfaces of the recipient bones and re-established a functional bone marrow organ-like system. These data suggested that MSC-mediated tissue regeneration led to a body structure extension, with the re-establishment of all functional components necessary for maintaining the bone and associated marrow organ. In addition, we found that the subcutaneous transplantation of another population of MSCs, the human periodontal ligament stem cells (PDLSCs), could form substantial amounts of collagen fibers and improve facial wrinkles in mouse. By contrast, bone marrow MSCs failed to survive at 8 weeks post-transplantation under the conditions used for the PDLSC transplantation. This study suggested that the mutual interactions between donor MSCs and recipient microenvironment determine long-term outcome of the functional tissue regeneration. Disclosure of potential conflicts of interest is found at the end of this article.

Animals↗
PubMed2006

NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF.

Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, yet the underlying mechanisms are poorly understood. Here we report that nuclear factor-kappaB (NF-kappaB) plays a crucial role in the osteolytic bone metastasis of breast cancer by stimulating osteoclastogenesis. Using an in vivo bone metastasis model, we found that constitutive NF-kappaB activity in breast cancer cells is crucial for the bone resorption characteristic of osteolytic bone metastasis. We identified the gene encoding granulocyte macrophage-colony stimulating factor (GM-CSF) as a key target of NF-kappaB and found that it mediates osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Moreover, we observed that the expression of GM-CSF correlated with NF-kappaB activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-kappaB in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-kappaB is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis.

Animals↗
PubMed2006

The mechanical phenotype of biglycan-deficient mice is bone- and gender-specific.

Biglycan (bgn) is a small leucine-rich proteoglycan (SLRP) enriched in the extracellular matrix of skeletal tissues. While bgn is known to be involved in the growth and differentiation of osteoblast precursor cells and regulation of collagen fibril formation, it is unclear how these functions impact bone's geometric and mechanical properties, properties which are integral to the structural function of bone. Because the genetic control of bone structure and function is both local- and gender-specific and because there is evidence of gender-specific effects associated with genetic deficiencies, it was hypothesized that the engineered deletion of the gene encoding bgn would result in a cortical bone mechanical phenotype that was bone- and gender-specific. In 11-week-old C57BL6/129 mice, the cortical bone in the mid-diaphyses of the femora and tibiae of both genders was examined. Phenotypic changes in bgn-deficient mice relative to wild type controls were assayed by four-point bending tests to determine mechanical properties at the whole bone (structural) and tissue levels, as well as analyses of bone geometry and bone formation using histomorphometry. Of the bones examined, bgn deficiency most strongly affected the male tibiae, where enhanced cross-sectional geometric properties and bone mineral density were accompanied by decreased tissue-level yield strength and pre-yield structural deformation and energy dissipation. Because pre-yield properties alone were impacted, this implies that the gene deletion causes important alterations in mineral and/or the matrix/mineral ultrastructure and suggests a new understanding of the functional role of bgn in regulating bone mineralization in vivo.

Animals↗
PubMed2006

Skeletal site-specific characterization of orofacial and iliac crest human bone marrow stromal cells in same individuals.

Autologous grafts from axial and appendicular bones commonly used to repair orofacial bone defects often result in unfavorable outcome. This clinical observation, along with the fact that many bone abnormalities are limited to craniofacial bones, suggests that there are significant differences in bone metabolism in orofacial, axial and appendicular bones. It is plausible that these differences are dictated by site-specificity of embryological progenitor cells and osteogenic properties of resident multipotent human bone marrow stromal cells (hBMSCs). This study investigated skeletal site-specific phenotypic and functional differences between orofacial (maxilla and mandible) and axial (iliac crest) hBMSCs in vitro and in vivo. Primary cultures of maxilla, mandible and iliac crest hBMSCs were established with and without osteogenic inducers. Site-specific characterization included colony forming efficiency, cell proliferation, life span before senescence, relative presence of surface markers, adipogenesis, osteogenesis and transplantation in immunocompromised mice to compare bone regenerative capacity. Compared with iliac crest cells, orofacial hBMSCs (OF-MSCs) proliferated more rapidly with delayed senescence, expressed higher levels of alkaline phosphatase and demonstrated more calcium accumulation in vitro. Cells isolated from the three skeletal sites were variably positive for STRO 1, a marker of hBMSCs. OF-MSCs formed more bone in vivo, while iliac crest hBMSCs formed more compacted bone that included hematopoietic tissue and were more responsive in vitro and in vivo to osteogenic and adipogenic inductions. These data demonstrate that hBMSCs from the same individuals differ in vitro and in vivo in a skeletal site-specific fashion and identified orofacial marrow stromal cells as unique cell populations. Further understanding of site-specific properties of hBMSCs and their impact on site-specific bone diseases and regeneration are needed.

Adolescent↗
PubMed2006

Dental pulp stem cells.

Postnatal stem cells have been isolated from a variety of tissues. These stem cells are thought to possess great therapeutic potential for repairing damaged and/or defective tissues. Clinically, hematopoietic stem cells have been successfully used for decades in the treatment of various diseases and disorders. However, the therapeutic potential of other postnatal stem cell populations has yet to be realized, because of the lack of detailed understanding of their stem cell characteristics at the cellular and molecular levels. Furthermore, there is limited knowledge of their therapeutic value at the preclinical level. Therefore, it is necessary to develop optimal strategies and approaches to overcome the substantial challenges currently faced by researchers examining the clinical efficacy of different postnatal stem cell populations. In this review, we introduce methodologies for isolating postnatal stem cells from human dental pulp and discuss their potential role in tissue regeneration.

Animals↗
PubMed2006

Mesenchymal stem cell-organized bone marrow elements: an alternative hematopoietic progenitor resource.

Bone marrow-derived mesenchymal stem cells (BMMSCs) are multipotent postnatal stem cells that have been used for the treatment of bone defects and graft-versus-host diseases in clinics. In this study, we found that subcutaneously transplanted human BMMSCs are capable of organizing hematopoietic progenitors of recipient origin. These hematopoietic cells expressed multiple lineages of hematopoietic cell associated markers and were able to rescue lethally irradiated mice, with successful engraftment in the recipient, suggesting a potential bone marrow (BM) resource for stem cell therapies. Furthermore, we found that platelet-derived growth factor (PDGF) promotes the formation of BMMSC-generated BM niches through upregulation of beta-catenin, implying that the PDGF pathway contributes to the formation of ectopic BM. These results indicate that the BMMSC-organized BM niche system represents a unique hematopoietic progenitor resource possessing potential clinical value.

Animals↗
PubMed2005

Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation.

Despite recent emerging evidence suggesting that cancer stem cells subsist in a variety of tumors, it is not yet fully elucidated whether postnatal stem cells are directly involved in tumorigenesis. We used murine bone marrow-derived mesenchymal stem cells (BMMSCs) as a model to test a hypothesis that tumorigenesis may originate from spontaneous mutation of stem cells. In this study, we demonstrated that murine BMMSCs, after numerous passages, obtained unlimited population doublings and proceeded to a malignant transformation state, resulting in fibrosarcoma formation in vivo. Transformed BMMSCs colonized to multiple organs when delivered systemically through the tail vein. Fibrosarcoma cells formed by transformed BMMSCs contained cancer progenitors, which were capable of generating colony clusters in vitro and fibrosarcoma in vivo by the second administration. The mechanism by which BMMSCs transformed to malignant cells was associated with accumulated chromosomal abnormalities, gradual elevation in telomerase activity, and increased c-myc expression. Moreover, BMMSCs and their transformed counterpart, fibrosarcoma-forming cells, demonstrated different sensitivity to anti-cancer drugs. BMMSCs/fibrosarcoma transformation system may provide an ideal system to elucidate the mechanism of how stem cells become cancer cells and to screen anti-sarcoma drugs.

Animals↗
PubMed2005

Defective osteogenesis of the stromal stem cells predisposes CD18-null mice to osteoporosis.

Osteogenesis by the bone marrow stromal stem cells (BMSSCs) supports continuous bone formation and the homeostasis of the bone marrow microenvironment. The mechanism that controls the proliferation and differentiation of BMSSCs is not fully understood. Here, we report that CD18, a surface protein present primarily on hematopoietic cells, but not on differentiated mesenchymal cells, is expressed by the stromal stem cells and plays a critical role in the osteogenic process. Constitutive expression of CD18 on BMSSCs using a retroviral promoter significantly enhances bone formation in vivo, whereas genetic inactivation of CD18 in mice leads to defective osteogenesis due to decreased expression of the osteogenic master regulator Runx2/Cbfa1. The defective osteogenesis of the CD18-null BMSSCs can be restored by expressing full-length, but not cytoplasmic domain-truncated, CD18. Radiographic analyses with dual-energy x-ray absorptiometry and 3D microcomputed tomography show that mice lacking CD18 have decreased bone mineral density and exhibit certain features of osteoporosis. Altogether, this work demonstrates that CD18 functions critically in the osteogenesis of BMSSCs, and thus lack of CD18 expression in the leukocyte adhesion deficiency patients may predispose them to osteoporosis.

Animals↗
PubMed2005

MEPE is downregulated as dental pulp stem cells differentiate.

UNLABELLED: Previous studies on dental pulp cell culture have described heterogenous mixtures of cells that differentiate into odontoblasts and form mineralized dentin. OBJECTIVE: The aim of this study was to characterize the matrix extracellular phosphoglycoprotein (MEPE) expression by dental pulp stem cells (DPSC), related to cell differentiation. DESIGN: DPSC differentiation to form mineralized nodules was characterized by Alizarin red staining and micro-Raman spectroscopy. Osteogenesis SuperArray analysis was used to broadly screen for osteogenesis-related genes altered by DPSC differentiation. Relative levels of expression of MEPE and DSP were determined by semiquantitative RT-PCR and Western blot. RESULTS: Mineral analysis showed that as DPSC differentiated, they formed a carbonated hydroxyapatite mineral. Differentiation was initially marked by upregulation by Runx2, TGFbeta-related genes, EGFR and genes involved in collagen metabolism. ALP activity first increased, as DPSCs reached confluence but later decreased when cells further differentiated three weeks after confluence. MEPE was the only marker that was downregulated as DPSCs differentiated. CONCLUSION: DPSC differentiation can be characterized by downregulation of MEPE as other markers of DPSC differentiation, such as DSP, are upregulated. Expression of MEPE related to DSP and can be used to monitor DPSC as they are used for studies of odontoblast differentiation, tissue engineering or vital pulp therapy. The downregulation of MEPE as DPSC differentiate, suggests that MEPE is an inhibitor of mineralization.

Biomarkers↗
PubMed2005

Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells.

The maintenance of bone marrow stromal stem cells (BMSSCs) is tightly controlled by the local microenvironment and by autocrine regulatory factors secreted by BMSSCs. To identify such factors, a cDNA subtraction library was generated from purified BMSSCs, based on their high expression of the STRO-1 antigen. Stromal-derived factor-1 (SDF-1) was one differentially expressed gene highly expressed by purified BMSSCs prior to culture. In vitro, immature preosteogenic cells expressed greater levels of SDF-1 when compared with mature cell types representative of osteoblasts and osteocytes/bone lining cells. Furthermore, SDF-1 expression was rapidly down-regulated when BMSSCs were cultured under osteoinductive conditions. BMSSCs were also shown to express functional cell surface SDF-1 receptors (CXCR4). Transduced BMSSC lines, secreting high SDF-1 levels, displayed an enhanced ability to form ectopic bone in vivo, in comparison with control BMSSC lines. Moreover, high SDF-1-expressing BMSSCs displayed an increased capacity for cellular growth and protection against interleukin-4-induced apoptosis. Similarly, fibroblast colony-forming units (CFU-Fs) also displayed increased growth and resistance to alpha-interferon-2a-induced apoptosis, in synergy with platelet-derived growth factor BB (PDGF-BB) and SDF-1 in vitro. These studies indicate that the chemokine, SDF-1, may play a role in the maintenance, survival, and osteogenic capacity of immature BMSSC populations.

Adult↗
PubMed2005

Skeletal stem cells in regenerative medicine.

Postnatal stem cells have been isolated from a variety of tissues and they are highly expected to have potentiality to be utilized for cell-based clinical therapies. Bone marrow stromal stem cells (BMSSCs) derived from bone marrow stromal tissue have been identified as a population of multipotent mesenchymal stem cells that are capable of differentiating into osteoblasts, adipocytes, chondrocytes, muscle cells, and neural cells. The most significant tissue regeneration trait of BMSSCs is their in vivo bone regeneration capability, which has been widely studied for understanding molecular and cellular mechanisms of osteogenesis, and, more importantly, developing into a stem-cell-based therapy. Recent studies further demonstrated that BMSSC-mediated bone regeneration is a promising approach for regenerative medicine in clinical trials. However, there are some fundamental questions that remain to be answered prior to successful utilization of BMSSCs in clinical therapy. For instance, how to maintain stemness of BMSSCs will be a critical issue for developing methodologies to propagate multi-potential stem cells in vitro, in order to allow the development of effective clinical therapies.

Animals↗
PubMed2004

A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells.

Caspase-3 is a critical enzyme for apoptosis and cell survival. Here we report delayed ossification and decreased bone mineral density in caspase-3-deficient (Casp3(-/-) and Casp3(+/-)) mice due to an attenuated osteogenic differentiation of bone marrow stromal stem cells (BMSSCs). The mechanism involved in the impaired differentiation of BMSSCs is due, at least partially, to the overactivated TGF-beta/Smad2 signaling pathway and the upregulated expressions of p53 and p21 along with the downregulated expressions of Cdk2 and Cdc2, and ultimately increased replicative senescence. In addition, the overactivated TGF-beta/Smad2 signaling may result in the compromised Runx2/Cbfa1 expression in preosteoblasts. Furthermore, we demonstrate that caspase-3 inhibitor, a potential agent for clinical treatment of human diseases, caused accelerated bone loss in ovariectomized mice, which is also associated with the overactivated TGF-beta/Smad2 signaling in BMSSCs. This study demonstrates that caspase-3 is crucial for the differentiation of BMSSCs by influencing TGF-beta/Smad2 pathway and cell cycle progression.

Adult↗
PubMed2003

Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow.

Previous studies have provided evidence for the existence of adult human bone marrow stromal stem cells (BMSSCs) or mesenchymal stem cells. Using a combination of cell separation techniques, we have isolated an almost homogeneous population of BMSSCs from adult human bone marrow. Lacking phenotypic characteristics of leukocytes and mature stromal elements, BMSSCs are non-cycling and constitutively express telomerase activity in vivo. This mesenchymal stem cell population demonstrates extensive proliferation and retains the capacity for differentiation into bone, cartilage and adipose tissue in vitro. In addition, clonal analysis demonstrated that individual BMSSC colonies exhibit a differential capacity to form new bone in vivo. These data are consistent with the existence of a second population of bone marrow stem cells in addition to those for the hematopoietic system. Our novel selection protocol provides a means to generate purified populations of BMSSCs for use in a range of different tissue engineering and gene therapy strategies.

Adipocytes↗