Mesenchymal Stem Cell Working Group
This Working Group explores novel activities of mesenchymal stem cells which will be exploited to develop effective, safe, and durable therapies for muscle, bone, cartilage and skin diseases. The basic scientists and physician scientists in this group collaborate to efficiently address important translational problems. Several researchers in the group exploit tissue bioengineering with stem cells to advance translation of the basic research advances into clinical treatments to repair skeletal tissues damaged in injury, disease and aging.
The Nurminskaya group examines novel approaches to control and enhance formation of the cartilage implants with clinically relevant mesenchymal stem cells. These studies employ novel protein coatings for electrospun nanofibrous scaffolds combined with use of specific small molecule regulators to promote cartilage formation. In addition, the group is interested in understanding the molecular mechanisms of the reduced regenerative capacity of articular cartilage in osteoarthritis. These results will contribute to the development of allogeneic “off-the-shelf” stem cell therapies to improve cartilage repair with autologous and allogeneic stem cells.
Publications: Shanmugasundaram S, Logan-Mauney S, Burgos K, Nurminskaya M. Tissue transglutaminase regulates chondrogenesis in mesenchymal stem cells on collagen type XI matrices.Amino Acids. 2012 Feb;42(2-3):1045-53.
Lin X, Shanmugasundaram S, Liu Y, Derrien A, Nurminskaya M, Zamora PO. B2A peptide induces chondrogenic differentiation in vitro and enhances cartilage repair in rats. J Orthop Res. 2012 Aug;30(8):1221-8.
The Stains group collaborates with Dr. Eugene Koh to examine the use of mesenchymal stem cells to overcome the inflammatory and catabolic environment of the joint during osteoarthritis. Further, we are looking to enhance the protective ability of these mesenchymal stem cells by taking advantage of their ability to establish direct cell-to-cell communication with host tissues. The ultimate goal is to use and to improve the efficacy of mesenchymal stem cells to slow down the progression of degenerative diseases, like osteoarthritis.
The Christy group has been focusing on two areas of the use of mesenchymal stem cells (MSCs) in regenerative reconstructive surgery. The first area has been the use of the RIA (Reamer Irrigator Aspirator) for efficient harvest of bone graft for reconstruction of critical-sized mandibular defects in a porcine model of craniofacial injury. The identification of MSCs within the aspirate and the potential expansion of these cells to augment the bony healing of the mandibular defects may translate to clinical therapy for facial trauma patients. The second focus of the lab is to continue to define the role of stem cells in vascularized composite allotransplantation (VCA) and the immunosuppressive protocols for tissue that includes bone. This work has the potential to enhance bone healing in patients with craniofacial trauma and improve immunoregulation in transplant recipients.
Dr. Eckert’s team has identified a small population of cancer initiating stem cells of squamous cell carcinomas. The laboratory has characterized these cells and found that they express epidermis and embryonic stem cell markers and generate aggressive tumors. Natural diety-derived agents target stem cell maintenance protein expression in these cells to reduce tumor-initiating cell survival. The laboratory is also examining the production of human keratinocytes from embryonic stem cells and the conversion of keratinocyte to embryonic stem cells. This work is in collaboration with Dr. Candace Kerr.
Publications: Richard L. Eckert, Gautam Adhikary, Sivaprakasam Balasubramanian, Ellen A. Rorke, Mohan C. Vemuri, Shayne E. Boucher, Jackie R. Bickenbach, Candace Kerr, Biochemistry of epidermal stem cells, Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1830, Issue 2, February 2013, Pages 2427–2434.
Dr. Fang’s group employs biochemical, cell biology and live cell imaging approaches to study the function of ubiquitin proteasome system (UPS) and autophagy. One of the lab’s current focuses is to define the mechanism of UPS and autophagy in protein quality control in the endoplasmic reticulum (ER) and its deregulation in Huntington’s disease. Another aspect of the research in the lab is to study the role of the ER membrane-anchored E3 ubiquitin ligase Hrd1 in the regulation of human embryonic stem cell differentiation. To translate the basic research to drug discovery, the lab is interested in establishing live cell based assays for high-content screening for compound modulators of E3 ubiquitin ligases and deubiquitinating enzymes as well as protein trans-ER membrane transport pathway.
Dr. Fisher heads The Tissue Engineering and Biomaterials Laboratory at UMCP which investigates biomaterials, stem cells, and bioreactors for the regeneration of lost tissues, particularly bone, cartilage, vasculature, and skeletal muscle. The lab's research focuses on the development of novel, implantable, biocompatible materials that can support the development of both adult progenitor and adult stem cells, and particularly examines the interaction between stem cells and vasculature as well as how biomaterials affect endogenous molecular signaling among embedded cell populations.
Dr. Hsieh’s group employs cellular engineering approaches to elucidate cell-matrix interactions, through a combination of biological manipulation and device design. In particular, his research team has recently been focused on the formation of the pericellular matrix during chondrogenic differentiation, cellular remodeling of collagen matrices, and stem cell behavior and differentiation in microgravity. Their work seeks to develop novel strategies for enhancing stem cell-based therapeutics for degenerative musculoskeletal conditions.
Dr. Keefer’s group studies mechanisms controlling development in mammalian embryos and stem cells. Her lab was the first to characterize and manipulate the expression of the pluripotency factor, NANOG, in goat and bovine embryos. They have also developed a bovine NANOG promoter reporter system that is able to faithfully reflect regulatory mechanisms controlling bovine NANOG expression in embryos and iPSCs. This system is a useful tool for monitoring maintenance of pluripotency as well as promoter interactions with other transcriptional factors. In collaboration with the laboratory of Dr. J. Desai (Mechanical Engineering, UMD), her lab has also demonstrated that the initial stages of differentiation could be distinguished by assessing the mechanical properties of mESC.
Publications: Keefer, C. L. and Desai, J. P. (2011). Mechanical Phenotyping of Stem Cells. Theriogenology 75:1426-1430.
Pillarisetti, A., Desai, J. P., Ladjal, H., Schiffmacher, A., Ferreira, A. and Keefer, C. L. (2011). Mechanical Phenotyping of Mouse Embryonic Stem Cells: Increase in Stiffness with Differentiation. Cell Reprogramming 13:371-380
Lei, L., Li, L., Du, F., Chen, C.H., Wang, H., and Keefer, C.L. (2013). Monitoring bovine fetal fibroblast reprogramming utilizing a bovine NANOG promoter-driven EGFP reporter system. Molecular Reproduction and Development. 2013 Mar; 80(3):193-203. doi: 10.1002/mrd.22147. Epub 2013 Jan 28.
The Lu-Chang group is interested in enhancing the efficiency of generation of induced pluripotent stem cells (iPSCs). We aim to reactivate the key pluripotency regulator, OCT4, through altering its epigenetic state. Thymine DNA glycosylase (TDG) is an essential multifunctional enzyme involved in DNA repair, DNA demethylation, and transcription regulation. It has been shown that TDG can activate OCT4. We have shown that SIRT1 (a member of class III NAD+-dependent histone/protein deacetylases) can activate OCT4 gene expression. We have demonstrated that TDG glycosylase activity is enhanced by interaction with SIRT1. Thus, we hypothesize that the expressing SIRT1 and TDG or employing their modulators will affect reprogramming. By using DNA repair enzymes and epigenetic regulators, the derived iPSCs should be high proliferative, tolerant to oxidative stress, and highly similar to ES cells.
Dr. Xu’s group, the Biomaterials and Tissue Engineering Division of the School of Dentistry, focuses on stem cells and tissue engineering, the development of novel bioactive and resorbable scaffolds and biomimetic and injectable carriers, the delivery of stem cells and growth factors for bone regeneration, and animal studies on dental and craniofacial repairs. Dr. Xu's group also develops smart nanocomposites and novel antibacterial dental materials for tooth restorations with caries inhibition and remineralization capabilities. His group uses multidisciplinary approaches, state-of-the-art methods and analyses techniques, as well as novel materials engineering principles. Dr. Xu’s group has published over 130 original articles in leading journals.
Dr. Yu develops artificial extracellular matrices (ECMs) for stem cell culture in both 2D and 3D. His current interest is to engineer ECMs with unnatural chirality to direct stem cell biology. Natural ECMs are made of homochiral L-peptides and D-saccharides. The artificial ECMs made by Dr. Yu’s group have a range of chirality compositions, including homochiral, heterochiral and racemic. The goal is to use chirality as a tool to guide stem cell proliferation and differentiation.
Publication: Hyland, L., Twomey, J., Vogel, S., Hsieh, A., Yu, Y. B. (2013) Enhancing biocompatibility of D oligopeptide hydrogels by negative charges. Biomacromolecules, 14, 406-412.
The Zaghloul lab is interested in understanding the molecular and developmental mechanisms that contribute to complex metabolic phenotypes, such as obesity and diabetes. To do this, we are using zebrafish and cell-based models to study how genes associated with these phenotypes contribute to the specification of cell types that are important to their onset. For example, we are interested in how pancreatic beta cell specification is altered with the loss of genes linked to type 2 diabetes. This type of understanding is important not only to understand how disruption of cell types specification during development can contribute to adult onset diseases, but it also allows us to model the production and maintenance of these cell types, a process that is important throughout life.
The Zalzman group studies the fundamental mechanisms controlling cellular immortality and telomere repair. For our study, we use adult mesenchymal stem cells (MSCs) as an in vitro model for aging and telomere damage. Our lab develops novel protocols to promote transient telomere rejuvenation in order to enhance the replicative life span and expansion potential of adult stem cells. This research will allow the large scale expansion of MSCs required for future therapies of numerous diseases that are currently candidates for MSC treatment.
Publications: Zalzman M, Falco G, Sharova LV, Nishiyama A, Thomas M, Lee SL, Stagg CA, Hoang HG, Yang HT, Indig FE, Wersto RP, Ko MS. Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature. 2010. 464(7290):858-63.
Dr. Zhang’s group has been studying several skeletal stem cells over the past decade, including mesenchymal stem cells (MSCs) and tendon stem cells. The major goal of his research is develop better strategies for isolation, characterization and use of these different stem cells in tissue repair and regeneration. Previously, they identified a unique MSC marker and demonstrated its utility in the isolation of MSCs from the bone marrow by cell sorting. They also identified tendon stem cells and established proof-of-principle for their use in tendon repair. Currently, his group is studying the role of embryonic origin in MSC proliferation, differentiation and signaling. The information generated will help design optimal stem cell-based therapies for human patients.