|  |  |  | | | | | pubmed: "regenerative medici... | | | | | | | | | | | | | | | | | | | Insights into neurogenesis and aging: potential therapy for degenerative disease? Future Neurol. 2010 Jul 1;5(4):527-541 Authors: Marr RA, Thomas RM, Peterson DA Neurogenesis is the process by which new neural cells are generated from a small population of multipotent stem cells in the adult CNS. This natural generation of new cells is limited in its regenerative capabilities and also declines with age. The use of stem cells in the treatment of neurodegenerative disease may hold great potential; however, the age-related incidence of many CNS diseases coincides with reduced neurogenesis. This review concisely summarizes current knowledge related to adult neurogenesis and its alteration with aging and examines the feasibility of using stem cell and gene therapies to combat diseases of the CNS with advancing age. PMID: 20806052 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Mesenchymal stem cell therapy regenerates the native bone-tendon junction after surgical repair in a degenerative rat model. PLoS One. 2010;5(8): Authors: Nourissat G, Diop A, Maurel N, Salvat C, Dumont S, Pigenet A, Gosset M, Houard X, Berenbaum F BACKGROUND: The enthesis, which attaches the tendon to the bone, naturally disappears with aging, thus limiting joint mobility. Surgery is frequently needed but the clinical outcome is often poor due to the decreased natural healing capacity of the elderly. This study explored the benefits of a treatment based on injecting chondrocyte and mesenchymal stem cells (MSC) in a new rat model of degenerative enthesis repair. METHODOLOGY: The Achilles' tendon was cut and the enthesis destroyed. The damage was repaired by classical surgery without cell injection (group G1, n = 52) and with chondrocyte (group G2, n = 51) or MSC injection (group G3, n = 39). The healing rate was determined macroscopically 15, 30 and 45 days later. The production and organization of a new enthesis was assessed by histological scoring of collagen II immunostaining, glycoaminoglycan production and the presence of columnar chondrocytes. The biomechanical load required to rupture the bone-tendon junction was determined. PRINCIPAL FINDINGS: The spontaneous healing rate in the G1 control group was 40%, close to those observed in humans. Cell injection significantly improved healing (69%, p = 0.0028 for G2 and p = 0.006 for G3) and the load-to-failure after 45 days (p<0.05) over controls. A new enthesis was clearly produced in cell-injected G2 and G3 rats, but not in the controls. Only the MSC-injected G3 rats had an organized enthesis with columnar chondrocytes as in a native enthesis 45 days after surgery. CONCLUSIONS: Cell therapy is an efficient procedure for reconstructing degenerative entheses. MSC treatment produced better organ regeneration than chondrocyte treatment. The morphological and biomechanical properties were similar to those of a native enthesis. PMID: 20805884 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | Tumor-Initiating Cells Are Rare in Many Human Tumors. Cell Stem Cell. 2010 Sep 3;7(3):279-282 Authors: Ishizawa K, Rasheed ZA, Karisch R, Wang Q, Kowalski J, Susky E, Pereira K, Karamboulas C, Moghal N, Rajeshkumar NV, Hidalgo M, Tsao M, Ailles L, Waddell TK, Maitra A, Neel BG, Matsui W Tumor-initiating cells (TICs) are defined by their ability to form tumors after xenotransplantation in immunodeficient mice and appear to be relatively rare in most human cancers. Recent data in melanoma indicate that the frequency of TICs increases dramatically via more permissive xenotransplantation conditions, raising the possibility that the true frequency of TICs has been greatly underestimated in most human tumors. We compared the growth of human pancreatic, non-small cell lung, and head and neck carcinomas in NOD/SCID and NSG mice. Although TIC frequency was detected up to 10-fold higher in NSG mice, it remained low (<1 in 2500 cells) in all cases. Moreover, aldehyde dehydrogenase-positive (ALDH(+)) and CD44(+)CD24(+) cells, phenotypically distinct cells enriched in TICs, were equally tumorigenic in NOD/SCID and NSG mice. Our findings demonstrate that TICs are rare in these cancers and that the identification of TICs and their frequency in other human malignancies should be validated via primary tumors and highly permissive xenotransplantation conditions. PMID: 20804964 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Formulation and characterization of silk sericin-PVA scaffold crosslinked with genipin. Int J Biol Macromol. 2010 Aug 27; Authors: Aramwit P, Siritientong T, Kanokpanont S, Srichana T A porous-three-dimensional scaffold shows several advantages in terms of tissue engineering since it can provide a framework for cells to attach, proliferate and form an extracellular matrix. Sericin, a by-product from the silk industry, can form a three-dimensional scaffold with PVA after freeze-drying but has a fragile structure. Glycerin (as a plasticizer) and genipin (a crosslinking agent) are necessary to make a strong and stable matrix. Our objective was to investigate the properties of a three-dimensional silk sericin and PVA scaffold with and without glycerin and genipin at various concentrations. SEM showed that adding glycerin into scaffold gave better uniformity and porosity. Smaller pore sizes and better uniformity were found as the concentration of genipin in the scaffold increased. The results of FTIR indicated that glycerin retained a high moisture content and had a major effect at 3 286cm(-1), indicating the presence of water molecule in the matrix structure. Adding genipin into the scaffold resulted in a higher degree of crosslinking or fewer free in-amino groups, as shown by the decrease in the stretching (=C-H) peak and absorption peaks around 1 370-1 650cm(-1), respectively. The sericin/PVA scaffold had a low water sorption capacity, but adding glycerin significantly increased this property. Genipin further enhanced the moisture absorption capacity of the scaffold and extended the time taken to reach equilibrium. After immersing the sericin/PVA scaffold into purified water, the scaffold completely dissolved within an hour, whereas the scaffolds containing glycerin or glycerin with 0.1% genipin swelled 8 and 11 times, respectively, compared with the initial stage after 6h of immersion. In terms of mechanical properties, the sericin/PVA/glycerin scaffold exhibited a similar compressive strength to the scaffold with a high genipin concentration, whereas a low concentration of genipin softened and reduced the compressive strength of the scaffold. A small amount of sericin was released from the scaffold and a higher concentration of genipin, resulting in less protein leaching compared to non-crosslinked sericin/PVA. The fraction of protein released from the sericin/PVA/glycerin scaffold was about 4%, with values of about 1% and 0.04% in the case of scaffolds with 0.01% and 0.1% genipin, respectively. All results indicated that the composition of the scaffolds had a significant effect on their physical properties, and that can easily be tuned to obtain scaffolds suitable for biological applications. PMID: 20804781 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Extrinsic regulation of satellite cell specification. Stem Cell Res Ther. 2010 Aug 26;1(3):27 Authors: Bentzinger CF, von Maltzahn J, Rudnicki MA ABSTRACT: Cellular commitment during vertebrate embryogenesis is controlled by an interplay of intrinsic regulators and morphogenetic signals. These mechanisms recruit a subset of cells in the developing organism to become the ancestors of skeletal muscle. Signals that control progression through the myogenic lineage converge on a battery of hierarchically organized transcription factors which modulate the cells to either remain in a primitive state or allow their commitment and differentiation into skeletal muscle fibers. A small population of cells will retain a largely unspecified state throughout development. Such stem cells, in conjunction with more committed myogenic progenitors, form a heterogeneous population that colonizes adult skeletal muscle as satellite cells. The satellite cell pool is responsible for the remarkable regenerative capacity of skeletal muscle. Similar to their counterparts during embryonic development, satellite cells are capable of self-renewal and can give rise to myogenic progeny. Impaired satellite cell homeostasis has been associated with numerous muscular disorders. Due to intense research efforts in the past two decades, the complex biology of muscle stem cells has now revealed some of its secrets and new avenues for the development of therapeutic molecules have emerged. In the present review we focus on the extrinsic mechanisms that control self-renewal, specification and differentiation of satellite cells and their significance for the development of biologic drugs. PMID: 20804582 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Mesenchymal stem cells in arthritis: role of bone marrow microenvironment. Arthritis Res Ther. 2010 Aug 23;12(4):135 Authors: Jorgensen C ABSTRACT: Based on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSCs) are intensively studied for regenerative medicine. Moreover, MSCs are potent immunomodulatory cells that occur through the secretion of soluble mediators including nitric oxide, transforming growth factor beta, and HLAG5. The MSCs, however, are also able to express inflammatory mediators such as prostaglandin E2 or IL-6. MSCs in the bone marrow are in close contact with T cells and B cells, and they regulate immunological memory by organizing defined numbers of dedicated survival niches for plasma cells and memory T cells in the bone marrow. The role of MSCs in arthritis remains controversial - in some studies, murine allogeneic MSCs are able to decrease arthritis; in other studies, MSCs worsen the local inflammation. A recent paper in Arthritis Research and Therapy shows that bone marrow MSCs have decreased osteoblastic potential in rheumatoid arthritis, which may be related to chronic inflammation or to loss of expression of IL-1 receptor agonist. That article raises the importance of the bone marrow microenvironment for MSC biology. PMID: 20804569 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Versican targeting by RNA interference suppresses aggregative growth of dermal papilla cells. Clin Exp Dermatol. 2010 Aug 27; Authors: Feng M, Yang G, Wu J Summary Background. Dermal papilla cells (DPCs) are specialized fibroblasts found in the hair follicle papilla, which are associated with the development and cycle regulation of hair follicles (HFs). DPCs exhibit a multilayer aggregative growth character, which is closely related to induction of HF formation. Versican, a large chondroitin sulphate proteoglycan and one of the major components of the extracellular matrix, is involved in the formation of HF. Methods. To confirm the relationship between versican and the aggregative growth of DPCs, we first induced and established an aggregative cell model in DPCs in vitro, with cells taken to passage 8. Simultaneously, aggregative passage 2 DPCs and nonaggregative passage 8 DPCs were selected as parallel controls. RNA interference (RNAi) targeted to versican was used in passage 2 DPCs using a lentiviral vector. Reverse transcriptase (RT)-PCR and western blotting were used to assay the expression of versican in DPCs. Results. RNAi targeted to versican efficiently suppressed the aggregative growth of passage 2 DPCs, and the inhibitory effect was significant 3 days after RNAi treatment. The mRNA and protein levels of versican were also downregulated in passage 2 DPCs, and were lower than levels in nonaggregative passage 8 DPCs. Notably, the aggregative growth of nonaggregative passage 8 DPCs was restored after induction in a 1 : 1 v/v mixture of fresh DMEM and medium recycled from a previous passage. Conclusion. Versican is a key gene for the aggregative growth of DPCs, and might be significant in the regeneration of HF. PMID: 20804505 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Review article: stem cell therapies for inflammatory bowel disease - efficacy and safety. Aliment Pharmacol Ther. 2010 Aug 19; Authors: GarcÃa-Bosch O, Ricart E, Panés J Background Drugs available for the treatment of inflammatory bowel disease fail to induce and maintain remission in a significant number of patients. Aim To assess the value of stem cell therapies for treatment of inflammatory bowel disease based on published studies. Methods Publications were identified through a MEDLINE search using the Medical Subject Heading terms: inflammatory bowel diseases, or Crohn's disease, or ulcerative colitis, and stem cell, or stromal cell or transplant. Results Haematopoietic stem cell therapy as a primary treatment for inflammatory bowel disease was originally supported by animal experiments, and by remissions in patients undergoing transplant for haematological disorders. Later, transplantation specifically performed for patients with refractory Crohn's disease showed long-lasting clinical remission and healing of inflammatory intestinal lesions. Use of autologous nonmyeloablative regimens and concentration of the procedures in centres with large experience are key in reducing treatment-related mortality. Initial trials of mesenchymal stem cell therapy with local injection in Crohn's perianal fistulas had positive results. Conclusions Autologous haematopoietic stem cell transplant changes the natural course of Crohn's disease, and may be a therapeutic option in patients with refractory disease if surgery is not feasible due to disease location or extension. PMID: 20804451 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Gap in stem cell funding could drive Australian brain drain. Nat Med. 2010 Aug;16(8):834 Authors: Dolgin E PMID: 20689532 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Lab-grown organs seen as remedy for long donor waitlists. Nat Med. 2010 Aug;16(8):834 Authors: Palmer R PMID: 20689531 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Temporal specification of blood progenitors from mouse embryonic stem cells and induced pluripotent stem cells. Development. 2010 Sep 1;137(17):2829-39 Authors: Irion S, Clarke RL, Luche H, Kim I, Morrison SJ, Fehling HJ, Keller GM The efficient and reproducible generation of differentiated progenitors from pluripotent stem cells requires the recapitulation of appropriate developmental stages and pathways. Here, we have used the combination of activin A, BMP4 and VEGF under serum-free conditions to induce hematopoietic differentiation from both embryonic and induced pluripotent stem cells, with the aim of modeling the primary sites of embryonic hematopoiesis. We identified two distinct Flk1-positive hematopoietic populations that can be isolated based on temporal patterns of emergence. The earliest arising population displays characteristics of yolk sac hematopoiesis, whereas a late developing Flk1-positive population appears to reflect the para-aortic splanchnopleura hematopoietic program, as it has reduced primitive erythroid capacity and substantially enhanced myeloid and lymphoid potential compared with the earlier wave. These differences between the two populations are accompanied by differences in the expression of Sox17 and Hoxb4, as well as in the cell surface markers AA4.1 and CD41. Together, these findings support the interpretation that the two populations are representative of the early sites of mammalian hematopoiesis. PMID: 20659975 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Variations of X chromosome inactivation occur in early passages of female human embryonic stem cells. PLoS One. 2010;5(6):e11330 Authors: Dvash T, Lavon N, Fan G X chromosome inactivation (XCI) is a dosage compensation mechanism essential for embryonic development and cell physiology. Human embryonic stem cells (hESCs) derived from inner cell mass (ICM) of blastocyst stage embryos have been used as a model system to understand XCI initiation and maintenance. Previous studies of undifferentiated female hESCs at intermediate passages have shown three possible states of XCI; 1) cells in a pre-XCI state, 2) cells that already exhibit XCI, or 3) cells that never undergo XCI even upon differentiation. In this study, XCI status was assayed in ten female hESC lines between passage 5 and 15 to determine whether XCI variations occur in early passages of hESCs. Our results show that three different states of XCI already exist in the early passages of hESC. In addition, we observe one cell line with skewed XCI and preferential expression of X-linked genes from the paternal allele, while another cell line exhibits random XCI. Skewed XCI in undifferentiated hESCs may be due to clonal selection in culture instead of non-random XCI in ICM cells. We also found that XIST promoter methylation is correlated with silencing of XIST transcripts in early passages of hESCs, even in the pre-XCI state. In conclusion, XCI variations already take place in early passages of hESCs, which may be a consequence of in vitro culture selection during the derivation process. Nevertheless, we cannot rule out the possibility that XCI variations in hESCs may reflect heterogeneous XCI states in ICM cells that stochastically give rise to hESCs. PMID: 20593031 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Parthenogenic blastocysts derived from cumulus-free in vitro matured human oocytes. PLoS One. 2010;5(6):e10979 Authors: McElroy SL, Byrne JA, Chavez SL, Behr B, Hsueh AJ, Westphal LM, Pera RA BACKGROUND: Approximately 20% of oocytes are classified as immature and discarded following intracytoplasmic sperm injection (ICSI) procedures. These oocytes are obtained from gonadotropin-stimulated patients, and are routinely removed from the cumulus cells which normally would mature the oocytes. Given the ready access to these human oocytes, they represent a potential resource for both clinical and basic science application. However culture conditions for the maturation of cumulus-free oocytes have not been optimized. We aimed to improve maturation conditions for cumulus-free oocytes via culture with ovarian paracrine/autocrine factors identified by single cell analysis. METHODOLOGY/PRINCIPAL FINDING: Immature human oocytes were matured in vitro via supplementation with ovarian paracrine/autocrine factors that were selected based on expression of ligands in the cumulus cells and their corresponding receptors in oocytes. Matured oocytes were artificially activated to assess developmental competence. Gene expression profiles of parthenotes were compared to IVF/ICSI embryos at morula and blastocyst stages. Following incubation in medium supplemented with ovarian factors (BDNF, IGF-I, estradiol, GDNF, FGF2 and leptin), a greater percentage of oocytes demonstrated nuclear maturation and subsequently, underwent parthenogenesis relative to control. Similarly, cytoplasmic maturation was also improved as indicated by development to blastocyst stage. Parthenogenic blastocysts exhibited mRNA expression profiles similar to those of blastocysts obtained after IVF/ICSI with the exception for MKLP2 and PEG1. CONCLUSIONS/SIGNIFICANCE: Human cumulus-free oocytes from hormone-stimulated cycles are capable of developing to blastocysts when cultured with ovarian factor supplementation. Our improved IVM culture conditions may be used for obtaining mature oocytes for clinical purposes and/or for derivation of embryonic stem cells following parthenogenesis or nuclear transfer. PMID: 20539753 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Genetically engineered liquid-crystalline viral films for directing neural cell growth. Langmuir. 2010 Jun 15;26(12):9885-90 Authors: Chung WJ, Merzlyak A, Yoo SY, Lee SW Designing biomimetic matrices with precisely controlled structural organization that provides biochemical and physical cues to regulate cell behavior is critical for the development of tissue-regenerating materials. We have developed novel liquid-crystalline film matrices made from genetically engineered M13 bacteriophages (viruses) that exhibit the ability to control and guide cell behavior for tissue-regenerating applications. To facilitate adhesion between the viruses and cells, 2700 copies of the M13 major coat protein were genetically engineered to display integrin-binding peptides (RGD). The resulting nanofiber-like viruses displaying RGD motifs were biocompatible with neuronal cells and could be self-assembled to form long-range-ordered liquid-crystalline matrices by a simple shearing method. The resulting aligned structures were able to dictate the direction of cell growth. Future use of these virus-based materials for regenerating target tissues in vivo would provide great opportunities for various tissue therapies. PMID: 20443557 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Patterning of mono- and multilayered pancreatic beta-cell clusters. Langmuir. 2010 Jun 15;26(12):9943-9 Authors: Mendelsohn AD, Bernards DA, Lowe RD, Desai TA Cluster-size dependent behavior of pancreatic beta-cells has direct implications in islet transplantation therapy for type I diabetes treatment. Control over the cluster size enables evaluation of cluster-size-dependent function, ultimately leading to the production of beta-cell clusters with improved transplant efficacy. This work for the first time demonstrates the use of microcontact-printing-based cell patterning of discrete two- and three-dimensional clusters of pancreatic beta-cells. Both single and multiple cell layers are confined to a 2D area by attaching to patterns of covalently linked laminin and not adhering to surrounding polyethylene glycol. Cell clusters were successfully formed within 24 h for printed patterns in the range 40-120 microm, and simple modulation of the initial cell seeding density leads to the formation of multiple cell layers. Semiquantitative fluorescence microscopy, X-ray photoelectron spectroscopy, and Fourier transform infrared spectroscopy were used to extensively characterize the surface chemistry. This technique offers exceptional control over cell cluster shape and size, and not only provides an effective tool to study the cluster-size-dependent behavior of pancreatic beta-cells but also has potential applicability to numerous other cell lines. PMID: 20218546 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Harnessing systems biology approaches to engineer functional microvascular networks. Tissue Eng Part B Rev. 2010 Jun;16(3):361-70 Authors: Sefcik LS, Wilson JL, Papin JA, Botchwey EA Microvascular remodeling is a complex process that includes many cell types and molecular signals. Despite a continued growth in the understanding of signaling pathways involved in the formation and maturation of new blood vessels, approximately half of all compounds entering clinical trials will fail, resulting in the loss of much time, money, and resources. Most pro-angiogenic clinical trials to date have focused on increasing neovascularization via the delivery of a single growth factor or gene. Alternatively, a focus on the concerted regulation of whole networks of genes may lead to greater insight into the underlying physiology since the coordinated response is greater than the sum of its parts. Systems biology offers a comprehensive network view of the processes of angiogenesis and arteriogenesis that might enable the prediction of drug targets and whether or not activation of the targets elicits the desired outcome. Systems biology integrates complex biological data from a variety of experimental sources (-omics) and analyzes how the interactions of the system components can give rise to the function and behavior of that system. This review focuses on how systems biology approaches have been applied to microvascular growth and remodeling, and how network analysis tools can be utilized to aid novel pro-angiogenic drug discovery. PMID: 20121415 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Repair of bone defect using bone marrow cells and demineralized bone matrix supplemented with polymeric materials. Curr Stem Cell Res Ther. 2010 Mar;5(1):49-56 Authors: Kurkalli BG, Gurevitch O, Sosnik A, Cohn D, Slavin S We present a novel, reverse thermo-responsive (RTR) polymeric osteogenic composite comprising demineralized bone matrix (DBM) and unmanipulated bone marrow cells (BMC) for repair of bone defects. The polymers investigated were low viscosity aqueous solutions at ambient temperature, which gel once they heat up and reach body temperature. Our goal to supplement DBM-BMC composite with RTR polymers displaying superior rheological properties, was to improve graft integrity and stability, during tissue regeneration. The osteogenic composite when implanted under kidney capsule of mice, proved to be biocompatible and biodegradable, with no residual polymer detected in the newly formed osteohematopoietic site. Implantation of the osteogenic composite into a large area of missing area of parietal bone of the skull of rats, resulted in an extensive remodeling of DBM particles, fully reconstituted hematopoietic microenvironment and well integrated normal flat bone within thirty days. The quality and shape of the newly created bone were comparable to the original bone and neither local or systemic inflammatory reactions nor fibrosis at the junction of the new and old calvarium could be documented. Furthermore, combined laser capture microdissection (LCM) technique and PCR analysis of male BMC in female rats confirmed the presence of male derived cells captured from the repaired/ regenerated flat bone defect. The use of active self sufficient osteogenic DBM-BMC composite supported by a viscous polymeric scaffold for purposive local hard tissue formation, may have a significant potential in enhancement of bone regeneration and repair following trauma, degenerative or inflamatory lesion, iatrogenic interventions and cosmetic indications. PMID: 19807659 [PubMed - indexed for MEDLINE] | | | | | | | | | |  | |  | |  |
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