Stem Cell Institute of New Jersey
 
 

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At UMDNJ: An Emergent World of Stem Cell Research

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Two years ago, New Jersey became the second state in the nation to legalize stem cell research. As part of its commitment to advancing both stem cell laboratory research and clinical applications, the New Jersey Commission on Science and Technology (NJCST) established a $5 million grant program. Seventy-one applications were received and 17 grants were awarded to scientists throughout the state, including nine to faculty members at UMDNJ. The grantees, each of whom received about $300,000, are seeking to answer critical questions about how stem cells work. The other two scientists, who each received $250,000 grants from the New Jersey Department of the Treasury in consultation with NJCST, are designing standard operating procedures for stem cell clinical trials.

 

stem cell group photo

Pictured from left to right: Debabrata Banerjee, PhD Joseph R. Bertino, MD, Randall D. McKinnon, PhD, Michael M. Shen, PhD, Yufang Shi, PhD, Richard S. Nowakowski, PhD Monica Roth, PhD, Ling Qin, PhD Not pictured: Junichi Sadoshima, MD, PhD Rick Cohen, PhD, Biagio Saitta, PhD

 

Debabrata Benerjee, PhDDebabrata Banerjee, PhD
Associate Professor, Departments of Medicine and Pharmacology; UMDNJ-Robert Wood Johnson Medical School
Member, The Cancer Institute of New Jersey

Q: Please describe your NJCST-funded research project.

A: We propose to investigate umbilical cord blood derived mesenchymal stem cells (MSCs) to develop pre-clinical strategies for tumor targeting. Although MSCs have been demonstrated to migrate to in vivo sites including bone marrow, tumor microenvironment and sites of injury and inflammation, the molecular basis of migration remains to be clarified. In order for MSCs to become effective cellular delivery vehicles for tumor therapy, improved understanding of the molecular mechanisms involved in migration of MSCs to tumor sites is necessary. Stromal derived factor 1(SDF-1) has been shown to be a major player in migration of MSCs as well as for other progenitor/stem cells to sites of hypoxia. Little information exists regarding other factors present in the tumor microenvironment that may play a part in the migration of MSCs to tumor sites.

Q: Why did you select stem cells as a focus of your clinical research?

A: Gene delivery to tumor cells has been a challenging problem in experimental therapeutics. Various methods for gene delivery to tumors have been explored including cellular methods. Mesenchymal stem cells, which give rise to bone cells, fat cells, etc., appear to be good candidates for tumor targeting as they have been shown to "home" to sites of injury and to tumors when administered systemically.

Q: How will this research add to our understanding of the potential viability of stem cells for treating diseases?

A: A better understanding of the molecular mechanisms involved in these processes will permit us to design strategies for improving targeting of human MSCs to tumor sites for therapeutic purposes.

 

Joseph R. Bertino, MDJoseph R. Bertino, MD
University Professor of Medicine and Pharmacology
UMDNJ-Robert Wood Johnson Medical School
Associate Director, The Cancer Institute of New Jersey

Q: Please describe your NJCST-funded research project.

A: Our project is focused on expanding umbilical cord blood (UCB) stem cells ex vivo, or outside the body, thus providing sufficient numbers for adult transplantation. Specific aims of this project include refining UCB expansion to maximize growth in the mouse model; assaying expanded UCB cells to assure the absence of potentially deleterious genetic alterations that might be selected for by expansion; fulfilling regulatory and good manufacturing practices for UCB expansion; development of the clinical trial; and analysis of the kinetics and dynamics of engraftment of different cell types after transplantation into humans with advanced
hematologic malignancies anticipated to benefit from transplant but who do not have alternate donor choices.

Q: Why did you select stem cells as a focus of your research?

A: We selected cord blood stem cells for the focus of our research because they are a plentiful source of cells that may be used to reconstitute bone marrow function following chemotherapy or radiation therapy. They are readily available from blood centers in New Jersey, and have the advantage over adult marrow stem cells in that a perfect tissue match is not necessary. However, a unit of umbilical cord blood has a sufficient number of stem cells to reconstitute children and small adults, but not enough stem cells to reconstitute an average adult. Techniques used for expansion of human fetal liver hematopoietic cells have been successfully applied to UCB expansion in my laboratory. Ex vivo expanded UCB mononuclear cells (MNCs) engraft (grow and mature) in a mouse model with quantitative characteristics consistent with clinically relevant UCB expansion.

Q: How will this research add to our understanding of the potential viability of stem cells for treating diseases?

A: If successful, this will widen the availability of stem cells for adult patients who do not have a sibling with a tissue match.

 

Randall D. McKinnon, PhDRandall D. McKinnon, PhD
Assistant Professor, Department of Surgery
UMDNJ-Robert Wood Johnson Medical School

Q: Please describe your NJCST-funded research project.

A: We will focus on how to manipulate stem cells and direct their maturation into specific brain cell types in a culture dish. Our focus is stem cells from the full term human placenta which are abundant, retrievable, carry none of the ethical concerns of embryonic stem cells, and can be preserved at birth for subsequent patient-specific tailored therapeutics. Our studies will determine their ability to generate specialized glial cells that produce myelin sheaths to insulate neuronal axons, the cell type which is destroyed in multiple sclerosis. We have made significant contributions to the literature on signal molecules (growth factors) that direct the maturation of these glial cells. This project, involving placental stem cell studies, will take advantage of our past work and devise strategies to generate glia for tailored cell therapeutics.

Q: Why did you select stem cells as a focus of your research?

A: Our research centers on ways to stimulate and augment endogenous repair mechanisms in conditions such as spinal cord injury and in neurodegenerative diseases such as multiple sclerosis. Stem cells present an exciting, innovative alternative approach with several advantages over traditional pharmaceutical or surgical therapeutic modalities. Patient-specific stem cells may be useful to
generate specific brain cell types for the treatment of neurotrauma and neurodegenerative conditions.

Q: How will this research add to our understanding of the science of stem cells and their potential for treating diseases?

A: We hope our work will help elucidate any potential these placental stem cells may have to improve brain repair.

 

Richard S. Nowakowski, PhDRichard S. Nowakowski, PhD
Professor, Department of Neuroscience and Cell Biology
New Jersey Professor of Spinal Cord Research
UMDNJ-Robert Wood Johnson Medical School

Q: Please describe your NJCST-funded research project.

A: We are examining the change in "stemness" of the proliferating cells of the developing brain. By "stemness" we mean the change in the potential of these cells as the brain changes during development. Using strategy from Systems Biology, we will capture specimens from different parts of the developing brain and at
different ages using a laser microdissection technique in order to obtain small samples. Then, we will use two microarray technologies on each sample. The first is the new, but now standard, microarray for analyzing messenger RNAs (mRNAs). The
available technology will let us assay for more than 40,000 genes simultaneously so we will be able to get a virtually complete picture of the gene expression in these cells. A fraction of the RNA specimen will also be analyzed using a second microarray that will let us measure all of the known microRNAs, small molecules that play an important regulatory role in cell functions. We will take the results from the two microarrays and analyze them first statistically and then with bioinformatic criteria to identify which microRNAs are involved in the regulation of which mRNAs. The bioinformatic analysis will identify the transcription factors that mediate these interactions. Ultimately, we should have an understanding of the "molecular circuitry" that is acting within the neurostem cells during brain development.

Q: Why did you select stem cells as a focus of your research?

A: Stem cells have been the focus of research in this lab for many years. We work on a particular class of stems cells - neurostem cells, i.e., the ones that build the nervous system during normal development and which we hope to be able to use someday to rebuild the nervous system after injury or disease. The addition of an understanding of the molecular controls on gene expression will be a big leap for the field and will link our work on cell behavior with genetic work done in other laboratories.

Q: How will this research add to our understanding of the science of stem cells and their potential viability for treating diseases?

A: This project will provide basic information that can be used by future researchers to control the proliferation and development of neurostem cells. We believe that with an understanding of the molecular circuitry of stemness we will someday be able to control the fate of neurostem cells precisely so that they can be used for brain repair after an injury or disease.

 

Yufang Shi, PhDYufang Shi, PhD
Professor, Department of Molecular Genetics,
Microbiology and Immunology
UMDNJ-Robert Wood Johnson Medical School

Q: Please describe your NJCST-funded research project.

A: There is a particular class of stem cells that can be grown from adult bone marrow called mesenchymal stem cells or MSCs. One unique feature of these cells is their ability to suppress immune responses. We have found that MSCs have a potent effect in decreasing the activity of lymphocytes, which are key cells of the immune system. Lymphocytes are part of a network of cells and proteins that interact to generate the immune responses that fight infections and cancer. They also are responsible for causing many diseases where the immune system incorrectly targets normal tissues; that is, autoimmune diseases. We hope to determine
exactly what kinds of interactions between the lymphocytes and MSCs cause their immunosuppressive effects. For example, do MSCs secrete proteins or have molecules on their surface that signal lymphocytes to quiet themselves, and if so, what are they and how do they act on the lymphocytes? We will then test if injected MSCs can reduce the severity of autoimmune diseases and prolong the survival of transplanted organs.

Q: Why did you select stem cells as a focus of your research?

A: For the past 20 years, I have studied many aspects of the immune system. I am especially interested in understanding the mechanisms of immune tolerance since it has so many ramifications for the treatment of many very debilitating diseases. When I learned that MSCs can induce immunologic tolerance, we immediately began studies in this fascinating area. As an immunologist, I am very interested in discovering the mechanism of this effect since it leads to immunologic tolerance. We hope one day to be able to use these cells for the treatment of autoimmune and allergy-driven diseases such as arthritis, MS, diabetes and asthma. These cells could also be useful to prevent the rejection of transplanted organs and other types of stem cells.

Q: How will this research add to our understanding of the science of stem cells and their potential viability for treating diseases?

A: Stem cells are very promising for the treatment of many diseases. Embryonic stem cells have received much attention lately, but stem cells derived from adult tissue have many advantages over embryonic cells. Not only can they give rise to many different kinds of tissues for repairing degenerated or damaged tissues, but MSCs also promote immunologic tolerance and so can potentially be used to treat immunological diseases. By learning the mechanisms through which MSCs affect the immune system, we will be better able to apply the use of stem cells for clinical disease treatment.

Monica Roth, PhD

Monica Roth, PhD
Professor, Department of Biochemistry
UMDNJ-Robert Wood Johnson Medical School

Q: Please describe your NJCST-funded research project.

A: Hematopoietic stem cells are ideal targets for human gene therapy. Hematopoietic stem cells used in autologous cell replacements can be protected from high dose chemotherapy by introduction of drug resistant genes. These genes are frequently introduced using retroviral vectors. However, the retroviral vectors are not efficient at targeting hematopoietic stem cells. Our laboratory has developed a method to select for productive retroviral entry using novel receptor proteins. The method involves screening a library of more than a million different retroviral vectors for productive infection of the targeted cell. This method serves as a means of targeting gene delivery to cells that are not well characterized, including hematopoietic stem cells. This ultimate goal of the project is to isolate a novel retroviral particle that efficiently and specifically can recognize and deliver genes to hematopoietic stem cells.

Q: Why did you select stem cells as a focus of your research?

A: My laboratory has focused on vector development for gene therapy. Cell therapy, in particular stem cell therapy, offers benefits beyond that of gene therapy. Our research aims at combining the power of gene therapy with that of stem cell therapy. The project allows us to apply recent progress in targeted retroviral entry to the field of hematopoietic stem cell research.

Q: How will this research add to our understanding of the science of stem cells and their potential viability for treating diseases?

A: The research addresses one of the major shortcomings in current techniques, the efficiencies in which retroviral-based vectors can infect hematopoietic stem cells. This is a major limitation for myeloprotective strategies against high dose chemotherapy, which include the introduction of drug resistance genes into cells through gene transfer.

 

Junichi Sadoshima, MD, PhD
Professor and Vice Chair
Department of Cell Biology and Molecular Medicine
UMDNJ-New Jersey Medical School
Associate Director, Cardiovascular Research Institute

Q: Please describe your NJCST-funded research project.

A: Although adult stem cells implanted into the heart can differentiate into heart cells, at present, the efficiency of such treatment has been far below expectation. One reason could be that the current stem cell treatment is not able to generate sufficient numbers of functional heart cells. Our goal is to find the mechanism by which the efficiency of adult stem cell differentiation into heart cells is dramatically improved. My laboratory has substantial experience in biochemical and molecular biological characterization of intracellular signaling events in the heart, including glycogen synthase kinase-3 and the Wnt signaling pathway, both of which are likely to be involved in adult stem cell differentiation. We also have a number of unique transgenic animal models, in which we can turn on and off the expression of our gene of interest in a setting of experimentally induced heart failure. We will test our hypothesis that specific modulation of intracellular signaling events can alter the efficiency of adult stem cell differentiation into heart cells and improve the heart function during heart failure.

Q: Why did you select stem cells as a focus of your research?

A: We are relatively new to the field of stem cell research. Despite advancement of pharmacotherapy, heart failure is still the number one cause of death in the U.S. Heart transplantation can save only a limited number of patients, about 2,000 a year. We need fundamental treatment for heart failure. Studies conducted in the field thus far have clearly shown that adult stem cells have an ability to regenerate broken hearts. The use of adult stem cells would avoid ethical issues relevant to embryonic stem cells and therapeutic cloning. Importantly, one can use one's own stem cells, which avoids immune responses. Furthermore, one can modify the function of adult stem cells in test tubes so that these cells can be used as a vehicle of gene therapy. Thus, we believe that adult stem cells would be the most promising source of cells to be used for regeneration of the heart.

Q: How will this research add to our understanding of the science of stem cells and their potential viability for treating diseases?

A: Elucidating the molecular mechanisms by which the adult stem cells differentiate into heart cells would allow us to develop novel strategies to facilitate regeneration of the heart, which we hope could become a fundamental treatment for a wide variety of heart diseases.

 

Michael M. Shen, PhDMichael M. Shen, PhD
Professor, Department of Pediatrics
UMDNJ-Robert Wood Johnson Medical School
Member, Center for Advanced Biotechnology and Medicine
Member, The Cancer Institute of New Jersey

Q: Please describe the project your NJCST grant is funding.

A: My laboratory is pursuing studies of embryonic stem cells as a logical outgrowth of our work on the molecular regulation of mouse embryogenesis. Our research investigates the molecular mechanisms by which embryonic stem cells remain in the undifferentiated state, and how they make their initial decisions to generate specific cell types once released from the undifferentiated state. The Nodal
signaling pathway is a likely regulator of these processes, but its precise functions are presently unknown.

Q: Why did you select stem cells as a focus of your research?

A: I have had a long-standing interest in embryonic stem cells and early mouse development, starting with my postdoctoral studies in the early 90s. This project builds on our work on mouse development, exploring the regulation of pluripotent stem cells of the early mouse embryo in vivo, and will allow us to extend that research into studying embryonic stem cells in culture.

Q: How will this project add to our understanding of the science of stem cells and their potential viability for treating disease states?

A: Our work does not focus on a specific disease, but rather on understanding the basic biological processes that regulate embryonic stem cell behavior. Any therapeutic use of stem cells will require understanding the molecular mechanisms of their directed differentiation into specific cell types. Increasing our knowledge of the mechanisms by which stem cell state is maintained in the pre-implanted embryo will also be relevant for improving the success rate of in vitro fertilization.

Ling Qin, PhD

Ling Qin, PhD
Instructor, Department of Physiology and Biophysics
UMDNJ-Robert Wood Johnson Medical School

Q: Please describe your NJCST-funded research project.

A: I hypothesize that EGFR (epidermal growth factor receptor) signaling plays an important role in regulating mesenchymal stem cell proliferation and the subsequent differentiation of these cells into multiple tissue cells, including osteoblasts. I also hypothesize that one mechanism for the parathyroid hormone's (PTH) action on osteoporosis might be through increasing expression of amphiregulin, therefore expanding the mesenchymal stem cell pool to achieve more osteoblasts in bone. I will use three approaches to test these hypotheses. First, I will test whether expression of EGFR is required for all mesenchymal stem cells. Second, I will study how EGFR signaling affects mesenchymal stem cell behaviors such as proliferation, multi-differentiation, mobility and maintenance of stemness and the underlying mechanisms for those effects. Third, I will use animal models to study whether PTH treatment increases the stem cell pool in mice through activating EGFR signaling.

Q: Why did you select stem cells as a focus of your research?

A: My research has focused on the PTH treatment of osteoporosis. PTH stimulates bone formation by acting through the bone forming cell, the osteoblast, but the molecular mechanism for PTH's action is still largely unknown. Using microarrays, I
identified more than 100 genes regulated by PTH in osteoblastic cells. Among those genes, amphiregulin, a member of the epidermal growth factor (EGF) family of ligands, caught my attention. PTH stimulates amphiregulin expression in a rapid and transient fashion. Further studies found that amphiregulin stimulates the proliferation of osteoblast stem cells and inhibits their differentiation. We know two facts. One is that amphiregulin binds with EGFR. Another is that bone marrow mesenchymal stem cell can grow in the culture dish as long as EGF, another ligand for EGFR, is present. After putting all this evidence together, I believe it is important to study the interactions among stem cells, PTH, and EGFR signaling.

Q: How will this research add to our understanding of the science of stem cells and their potential viability for treating diseases?

A: Bone marrow-derived mesenchymal stem cells (BMMSC) have many advantages as candidates for tissue repair and gene therapy. They are easily expanded in vitro and still have the potential to differentiate into many tissue cells. Their low immunogenic property makes them ideal for transplantation. It is particularly interesting to study EGFR signaling since EGF is cheap and can be used to expand BMMSC in the culture dish. To my knowledge, PTH is the only known FDA-approved therapy that has the potential to regulate BMMSCs in vivo. Therefore, the results from this application could be quickly translated into clinical studies.

 

Rick Cohen, PhD
Assistant professor of medicine
UMDNJ-Robert Wood Johnson Medical School

Q: Please describe your NJCST-funded research project.

A: Primarily, the project's focus is to provide hands-on training to New Jersey investigators so that they can learn how to grow human embryonic stem (ES) cells. While that sounds trivial, there is an art to working with these cells that can only really be demonstrated.To help in this program, my collaborators from the Technion, which include Dr. Michal Amit, will join the group of local instructors to lead this training. Since Drs. Amit and Joseph Itskovitz have been working with ES cells since the mid-90s, they bring invaluable experience to the project. In addition to growing ES cells, we also teach other techniques for downstream analysis such as real-time PCR, cytogenetics, imaging, and others. In between the two yearly training sessions, we also supply technical support to labs beginning projects. This is in the form of on-line documentation or as site visits to help establish a new project or lab. All of this effort is aimed at expanding the numbers of scientists in this field and providing an avenue for New Jersey investigators to become fundable in this growing area. I also will be developing new technology to be implemented in the next course; for example, genetic reprogramming through transfer of genes using safe viral tools, or even techniques for micro-manipulation of cells.

Q: Why did you select stem cells as a focus of your research?

A: This was an ongoing focus in my research lab, which examines the ability of adult and embryonic stem cells to become brain-related cells. Part of my responsibility as a scientist is to do research, but it is also to educate. This project fulfills both of those needs.

Q: How will this research add to our understanding of the science of stem cells and their potential for treating diseases?

A: This project will provide the training for others to pursue those goals directly. However, I maintain an interest in neural differentiation of ES cells, and therefore, the focus of most of the applications will be to generate new brain cells. Since the nervous system is one of the organs we can't transplant, this research will help determine new avenues to create transplantable stem cells for diseases such as multiple sclerosis or spinal cord injury.

 

Biagio Saitta, PhD
Associate professor of medicine
UMDNJ-Robert Wood Johnson Medical School
Associate professor
Coriell Institute of Medical Research
Laboratory of Stem Cell and Matrix Biology

Q: Please describe your NJCST-funded research project.

A: Cardiovascular disease impacts millions of lives worldwide. Heart tissue responds to damage with scarring, fibrosis, and hypertrophy. The resulting loss of function limits the quality of life for most patients. Transplants are possible for many cardiac conditions, but donors are limited. Our central hypothesis is that the introduction of stem cells affects pathologic remodeling of heart tissue by reducing the fibrotic response through the modulation of extracellular matrix (ECM) gene expression. The use of an in vitro model is necessary to define the molecular mechanisms for the demonstrated effects of mesenchymal stem cells (MSCs). The rationale behind this approach is that the ECM is integrally involved in cell migration, wound healing and fibrosis. We have successfully and reproducibly isolated MSCs from neonatal umbilical cord blood (UCB) obtained from the New Jersey Cord Blood Bank, housed at the Coriell Institute. These cells are capable of specializing into multiple lineages, including cardiac cells. In this proposal, we will use an in vitro model of myocardial damage to study the response of MSCs to cardiac damage. The secretion of ECM proteins such as collagens and matrix metalloproteinases are seen in pathologic remodeling of the ventricle that follows infarct. ECM molecules are also the major component of fibrotic scars. Our approach will allow the identification of specific secreted factors and changes in ECM gene expression that result from stem cell response. Dr. Steven Hollenberg, director of the coronary care unit at Cooper Hospital, and Dr. Joseph Parrillo, director of the Cooper Heart Institute, are
collaborators.

Q: Why did you select stem cells as a focus of your research?

A: The new field of regenerative medicine utilizes multi-potent stem cells as a promising strategy to heal damaged tissue and preserve or regain function. MSCs from bone marrow target damaged myocardium in animal models of ischemic heart disease. Infusions of such adult stem cells limit fibrosis and improve function leading to the first U.S. clinical trials using allogenic adult MSCs to treat patients with heart attacks. However, the mechanisms that stem cells use to improve and support damaged myocardium remain largely unknown. We will use MSCs derived from human UCB as an uncontroversial cell and tissue resource for cardiovascular disease.

Q: How will this project add to our understanding of the science of stem cells and their potential viability for treating disease states?

A: Modulating and understanding the ECM protein changes promoted by MSCs can lead to information that will be directly relevant for management of myocardial infarction. These studies also can provide important new information on the action of MSCs and new targets for therapeutic discovery. UCB is enriched for these cells, is continuously available, requires less stringent compatibility matching, and comes from a varied ethnic population, making it a highly desirable source for transplant purposes.