About
81
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Introduction
Current institution
Additional affiliations
January 1992 - December 1997
January 2003 - January 2010
Position
- Professor (Assistant)
Description
- Characterization of adult human stem cells and biomaterials for bone regeneration.
April 2010 - present
Publications
Publications (81)
There has been extensive exploration of how cells may serve as advanced therapy medicinal products to treat skeletal pathologies. Osteoblast progenitors responsible for production of extracellular matrix that is subsequently mineralized during bone formation have been characterised as a rare bone marrow subpopulation of cell culture plastic adheren...
There is a "goldilocks" aspect to potency assays. On the one hand, a comprehensive evaluation of the cell product with detailed quantitative measurement of the critical quality attribute/s of the desired biological activity is required. On the other hand, the potency assay benefits from simplification and lean approaches that avoid unnecessary comp...
Potency assays represent crucial experiments at the hub of the comprehensive complexity surrounding cell therapy. Moreover, numerous factors beyond biological and scientific considerations are involved in achieving successful potency assays that fulfil regulatory authority approval for a new advanced therapy medicinal product. Though this can mean...
This volume of the Springer book series Advances in Experimental Medicine and Biology covers potency assays, one of the most complex yet fundamental evaluations that critically influence stem cell regenerative medicine. Developing potency assays for cell-based medicinal products comes with numerous challenges due to the highly specialised nature of...
A long-shared evolutionary history is congruent with the multiple roles played by purinergic signaling in viral infection, replication and host responses that can assist or hinder viral functions. An overview of the involvement of purinergic signaling among a range of viruses is compared and contrasted with what is currently understood for SARS-CoV...
This review conjugates the current knowledge of purinergic signaling in cancer biology with techniques involving nanomaterials to increase anticancer immune responses.
Potency assays are critical for regenerative medicine, addressing the known challenge of functional heterogeneity among human multipotent stromal cells (hMSC). Necessary laboratory cell expansion allows analysis before implantation in the patient. Levels of induction of five signature gene biomarkers, ALPL, COL1A2, DCN, ELN and RUNX2, constituted a...
GOPY is a free and open-source Python tool specifically written to automate the generation of 2D graphene-based molecular models such as pristine graphene (PG) and several graphene derivatives i.e. graphene oxide (GO), reduced graphene oxide (rGO), aminated polyethylene glycol functionalised reduced graphene oxide (rGO-PEG-NH2), and N-doped graphen...
Less is more: Corroborating a genomic biomarker identifying human bone marrow multipotent stromal cells with high scalability Addressing the problem of heterogeneity among primary isolates of human bone marrow-derived multipotent stromal cells (hBMSC), the recent study corresponded by Cool and Stanton et al identified a bio-marker correlated with e...
As graphene oxide-based oligonucleotide biosensors improve, there is a growing need to explore their ability to retain high sensitivity for low target concentrations in the context of biological fluids. Therefore, we innovatively combined assay milieu factors that could influence the key performance parameters of DNA hybridization and graphene oxid...
Graphene and its functionalised derivatives are transforming the development of biosensors that are capable of detecting nucleic acid hybridization. Using a Molecular Dynamics (MD) approach, we explored single-stranded or double-stranded deoxyribose nucleic acid (ssDNA or dsDNA) adsorption on two graphenic species: graphene oxide (GO) and reduced g...
Abstract Diverse properties of graphenic materials have been extensively explored to determine properties that make good electrochemical nanomaterial-based biosensors. These are reviewed by critically examining the influence of graphene nano-morphology, lattice defects and conductivity. Stability, reproducibility and fabrication are discussed toget...
We have investigated the influence exerted by the concentration of graphene oxide (GO) dispersion as a modifier for screen printed carbon electrodes (SPCEs) on the fabrication of an electrochemical biosensor to detect DNA hybridization. A new pretreatment protocol for SPCEs, involving two successive steps in order to achieve a reproducible depositi...
A main challenge for optical graphene-based biosensors detecting nucleic acid is the selection of key parameters e.g. graphenic chemical structure, nanomaterial dispersion, ionic strength, and appropriate molecular interaction mechanisms. Herein we study interactions between a fluorescein-labelled DNA (FAM-DNA) probe and target single-stranded comp...
Regenerative medicine is challenged by the need to conform to rigorous guidelines for establishing safe and effective development and translation of stem cell-based therapies. Counteracting widespread concerns regarding unproven cell therapies, stringent cell-based assays seek not only to avoid harm but also to enhance quality and efficacy. Potency...
Technological advances in engineering and cell biology stimulate novel approaches for medical treatment, in particular cell-based therapy. The first cell-based gene therapy against cancer was recently approved by the US Food and Drug Administration. Progress in cancer diagnosis includes a blood test detecting five cancer types. Numerous stem cell p...
Focus on the Warburg effect, initially descriptive of increased glycolysis in cancer cells, has served to illuminate mitochondrial function in many other pathologies. This review explores our current understanding of the Warburg effect’s role in cancer, diabetes and ageing. We highlight how it can be regulated through a chain of oncogenic events, a...
Background aims:
Numerous cellular models have been developed to investigate calcification for regenerative medicine applications and for the identification of therapeutic targets in various complications associated with age-related diseases. However, results have often been contradictory due to specific culture conditions, cell type ontogeny and...
Regeneration of atrophied alveolar bone prior to insertion of dental implants is a major challenge for oral and maxillo- facial surgery. It has been reported that Bone Marrow (BM) derived Mesenchymal Stromal Cells (MSC) retain thera- peutic potential for bone regeneration.
In the present study, a preclinical mini-pig model simulating the clinical s...
Adult human bone marrow stromal cells (hBMSC) cultured for cell therapy require evaluation of potency and stability for safe use. Chromosomal aberrations upsetting genomic integrity in such cells have been contrastingly described as "Limited" or "Significant". Previously reported stepwise acquisition of a spontaneous neoplastic phenotype during thr...
Graphene research, already prized, is nonetheless challenged to provide material advantages that bring about unique and novel applications rather than simply an improved substitute to existing materials. Arguably driving significant progress are new approaches to its manufacture including combination with other atoms and nanobiocomposite materials...
In skeletal regeneration approaches using human bone marrow derived mesenchymal stro-mal cells (hBM-MSC), functional evaluation before implantation has traditionally used bio-markers identified using fetal bovine serum-based osteogenic induction media and time courses of at least two weeks. However, emerging pre-clinical evidence indicates donor-de...
qRT-PCR Biomarker mRNA expression in all donor cells.
(XLSX)
Histological Bone quantification.
(XLSX)
Hierarchical cluster correlation with bone formation.
(XLSX)
qRT-PCR COL1A2 mRNA expression in donor#6 cells.
(XLSX)
Alizarin Red and Von Kossa Stain quantification.
(XLSX)
With constant scientific development of the underlying disciplines, consideration of optimal Biomaterial qualities becomes a work in progress rather than a comprehensively resolved issue. So the definition of Biomaterials provided by the 1982 Consensus Development Conference on the Clinical Applications of Biomaterials held at the National Institut...
Sarcomas are frequent tumors in children and young adults that, despite a relative chemo-sensitivity, show high relapse rates with up to 80% of metastatic patients dying in 5 years from diagnosis. The real ontogeny of sarcomas is still debated and evidences suggest they may derive from precursors identified within mesenchymal stromal/stem cells (MS...
We recently described conditions for safe 18-h manufacturer-to-patient transportation of freshly harvested hBM-MSC expanded under cGMP protocols using human platelet lysate (hPL), that allowed prompt use as an advanced therapeutic medicinal product. Here we outline important considerations when comparing different transportation conditions, highlig...
Successful preliminary studies have encouraged a more translational phase for stem cell research. Nevertheless, advances in the culture of human bone marrow derived mesenchymal stromal/stem cells (hBM-MSC) and osteoconductive qualities of combined biomaterials can be undermined if necessary cell transportation procedures prove unviable. We aimed to...
Mesenchymal stromal/stem cells (MSCs) reveal progenitor cells-like features including proliferation and differentiation capacities. One of the most historically recognized sources of MSC has been the bone marrow, while other sources recently include adipose tissue, teeth, bone, muscle, placenta, liver, pancreas, umbilical cord, and cord blood. Freq...
Mesenchymal stromal/stem cells (MSC) are adult multipotent progenitors with fibroblast-like morphology able to differentiate into adipocytic, osteogenic, chondrogenic, and myogenic lineages. Due to these properties, MSC have been studied and introduced as therapeutics in regenerative medicine. Preliminary studies have also shown a possible involvem...
Mise en abyme meaning "placed into abyss or infinite recurrence" is an apt paradigm for the relentless growth of sarcoma cells. Its alternative meaning, "self-reflexive embedding" fits the central role attributed to cancer stem cells (CSCs). Diversely sourced and defined, mesenchymal stem cells (MSCs) may be the cells of sarcoma origin, evolve a CS...
Resistance to radiation therapy remains a serious impediment to cancer therapy. We previously reported heterogeneity for clonogenic survival when testing in vitro radiation resistance among single-cell derived clones from a human mesenchymal cancer stem cell model (hMSC). Here we aimed to determine whether this heterogeneity persisted in tumours es...
Time-lapse phase contrast photomicrography of the cord-morphogenesis induced within 72 hours by serum deprivation (at 0 hours) in a monolayer of hMSC-TERT20-BD11 cells.
(MP4)
Background:
Acquisition of a blood supply is fundamental for extensive tumor growth. We recently described vascular heterogeneity in tumours derived from cell clones of a human mesenchymal stem cell (hMSC) strain (hMSC-TERT20) immortalized by retroviral vector mediated human telomerase (hTERT) gene expression. Histological analysis showed that cel...
A tumor represents a complex structure containing malignant cells strictly coupled with a large variety of surrounding cells constituting the tumor stroma (TS). In recent years, the importance of TS for cancer initiation, development, local invasion and metastases has become increasingly clear allowing the identification of TS as one of the possibl...
CONSORT Checklist
(0.24 MB DOC)
Danish Medicines Agency - Trial Protocol (Danish version)
(0.13 MB DOC)
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among premenopausal women, who often develop insulin resistance. We tested the hypothesis that insulin resistance in skeletal muscle of patients with polycystic ovary syndrome (PCOS) is an intrinsic defect, by investigating the metabolic characteristics and gene expression of in...
The creation of complex tissues and organs is the ultimate goal in tissue engineering. Engineered morphogenesis necessitates spatially controlled development of multiple cell types within a scaffold implant. We present a novel method to achieve this by adhering nanoparticles containing different small-interfering RNAs (siRNAs) into nanostructured s...
Immunotherapy holds great potential for disseminated cancer, and cancer-germline (CG) antigens are among the most promising tumor targets. They are widely expressed in different cancer types and are essentially tumor-specific, since their expression in normal tissues is largely restricted to immune-privileged sites. Although the therapeutic potenti...
Osteoblastic differentiation of human mesenchymal stem cells (hMSC) in monolayer culture is artefactual, lacking an organized bone-like matrix. We present a highly reproducible microwell protocol generating three-dimensional ex vivo multicellular aggregates of telomerized hMSC (hMSC-telomerase reverse transcriptase (TERT)) with improved mimicry of...
The ability of bone marrow stromal cells (BMSCs) to differentiate into osteoblasts is being exploited in cell-based therapy for repair of bone defects. However, the phenotype of ex vivo cultured BMSCs predicting their bone-forming capacity is not known. Thus we employed DNA microarrays comparing two human bone marrow stromal cell (hBMSC) population...
Cancer-germline antigens are promising targets for cancer immunotherapy, but whether such therapies will also eliminate the primary tumor stem cell population remains undetermined. We previously showed that long-term cultures of telomerized adult human bone marrow mesenchymal stem cells can spontaneously evolve into tumor-initiating, mesenchymal st...
Sarcomas display varied degrees of karyotypic abnormality, vascularity and mesenchymal differentiation. We have reported that a strain of telomerized adult human bone marrow mesenchymal stem cells (hMSC-TERT20) spontaneously evolved a tumorigenic phenotype after long-term continuous culture. We asked to what extent our hMSC-TERT20 derived tumors re...
Allelic loss at chromosome 9q31-34 is a frequent event in many lymphoproliferative malignancies. Here, we examined DBC1 at 9q33.1 as a potential target in lymphomagenesis. DBC1 is a putative tumor suppressor that has been shown to be involved in the regulation of cell growth and programmed cell death. The methylation status of the DBC1 promoter CpG...
When implanted into immunodeficient mice, human embryonic stem cells (hESCs) give rise to teratoma, tumor-like formations containing tissues belonging to all three germ layers. The ability to form teratoma is a sine qua non characteristic of pluripotent stem cells. However, limited data are available regarding the effects of implantation site and t...
Protein complexes are dynamic entities; identification and quantitation of their components is critical in elucidating functional roles under specific cellular conditions. We report the first quantitative proteomic analysis of the human cap-binding protein complex. Components and proteins associated with the translation initiation eIF4F complex tha...
This chapter provides an overview of the proteomic advances and highlights the aspects for practical consideration when investigating human cells, given a very broad number of alternative preparatory methods for determining protein content and function. A genome represents the entire complement of genetic material in a chromosome set, with a well-d...
To the Editor:
Rubio et al. ( [1][1]) reported in Cancer Research that adipose tissue–derived stem cells acquired a transformed phenotype after long-term culture in vitro . This article has been cited together with our article published in the same issue ( [2][2]) as evidence for the malignant
Long-term cultures of telomerase-transduced adult human mesenchymal stem cells (hMSC) may evolve spontaneous genetic changes leading to tumorigenicity in immunodeficient mice (e.g., hMSC-TERT20). We wished to clarify whether this unusual phenotype reflected a rare but dominant subpopulation or if the stem cell origin allowed most cells to behave as...
Human bone marrow mesenchymal stem cells (hMSC) represent a population of stem cells that are capable of differentiation into multiple lineages. However, these cells exhibit senescence-associated growth arrest and phenotypic changes during long-term in vitro culture. We have recently demonstrated that overexpression of human telomerase reverse tran...
Human bone marrow mesenchymal stem cells (hMSC) represent a population of stem cells that are capable of differentiation into multiple lineages. However, these cells exhibit senescence-associated growth arrest and phenotypic changes during long-term in vitro culture. We have recently demonstrated that overexpression of human telomerase reverse tran...
The use of human telomerase reverse transcriptase (hTERT)-immortalized cells in tissue engineering protocols is a potentially important application of telomere biology. Several human cell types have been created that overexpress the hTERT gene with enhanced telomerase activity, extended life span and maintained or even improved functional activitie...
The neoplastic process may involve a cancer stem cell. This concept has emerged largely from the careful analysis of tumour biopsy systems from haematological, breast and brain tumours. However, the experimental systems necessary to provide the cellular and molecular evidence to support this important concept have been lacking. We have used adult m...
Transforming growth factor-beta(1) (TGF-beta(1)) induces alpha-smooth muscle actin (alpha-SMA) and collagen synthesis in fibroblast both in vivo and in vitro and plays a significant role in tissue repair and the development of fibrosis. During these processes the fibroblasts differentiate into activated fibroblasts (so called myofibroblasts), chara...
Sensitivity to oestrogens and apoptosis are critical determinants of the development and progression of breast cancer and reflect closely linked pathways in breast epithelial cells. For example, induction of BCL-2 oncoprotein expression by oestrogen contributes to suppression of apoptosis and BCL-2 and oestrogen receptor (ER) are frequently co-expr...
The expression of cyclin-dependent kinase inhibitor p27kip1 in human tumors and normal tissues was investigated using a panel of novel anti-p27kip1 mAbs. An inverse correlation between expression of p27kip1 and cell proliferation was generally observed after analyzing its expression in 25 different normal human tissues. In some
highly proliferative...
Introduction of simian virus 40 T antigen into rodent fibroblasts gives rise to cells that can proliferate indefinitely but are dependent upon it for maintenance of their growth once the normal mitotic life span has elapsed. Inactivation of T antigen in these immortalized cells causes rapid and irreversible cessation of growth. To determine whether...
Genes of the ras family of dominant transforming genes are frequently activated by specific point mutations in common human epithelial malignancies and also in many experimental tumour models. Testing of the hypothesis that ras activation is a critical event in tumorigenesis involves reconstruction of genetic events in vitro using appropriate epith...
Activating mutations of the ras oncogene family occur at high frequency in all stages of thyroid tumorigenesis, both human and experimental. To test the causal nature of this association, and to investigate the biological role of ras mutation, we introduced a mutant c-Ha-ras gene into normal rat thyroid follicular cells using an ecotropic retrovira...
To investigate the role of ras mutations in thyroid epithelial tumorigenesis, we introduced wild-type or mutant v- or c-Ha-ras genes into a sub-cloned rat thyroid follicular epithelial cell line using retroviral vectors and a neutral selection method (G418 resistance). Mutant, but not wild-type, ras induced a spectrum of clonal phenotypes. Interest...
To overcome the difficulty of assessing oncogene action in human epithelial cell types, such as thyroid, which have limited proliferative potential in culture, we have explored the use of temperature-sensitive (ts) mutants of simian virus 40 (SV40) early region to create conditionally immortalized epithelial cell lines. Normal primary cultures of h...
To overcome the difficulty of assessing oncogene action in human epithelial cell types, such as thyroid, which have limited proliferative potential in culture, we have explored the use of temperature-sensitive (ts) mutants of simian virus 40 (SV40) early region to create conditionally immortalized epithelial cell lines. Normal primary cultures of h...
A recombinant murine retroviral vector encoding the SV40 virus large T antigen was used to infect stably an immortal line of differentiated rat thyroid epithelial cells, FRTL-5. Expression of SV40 T transformed these cells to anchorage independence and tumorigenicity but did not alter morphology or abolish tissue-specific functions and growth facto...
