Cellular and Molecular Biology, Physiology and Biotechnology Branch
Division of Basic and Translational Sciences
OBJECTIVE
We are seeking Concept Clearance for a Request for Applications (RFA). The purpose of this RFA is to foster research on embryonic and adult stem cell biology that could help elucidate the complex events that occur during oral, dental, and craniofacial development and disease as well as the repair and restoration of affected tissues. This initiative will focus on:
- the use of human embryonic stem cell lines listed in the NIH Human Embryonic Stem Cell registry. These cell lines can be used for examining mechanisms of progenitor cell differentiation and may also have characteristics that make them potentially useful for stem cell-based therapy;
- progenitor cells of the orofacial ectoderm and the cranial neural crest-derived mesenchyme, whose interaction during embryonic development gives rise to the craniofacial tissues including teeth, salivary glands, cartilage, bone, peripheral nerves, oral epithelium and smooth muscle; and
- adult stem cells in the orofacial and other body tissues (e.g., bone marrow, fat, blood) that have the ability to give rise to oral, dental, and craniofacial tissues and organs.
Because our current understanding of gene expression patterns during developmental stages comes from studies conducted in mice and other model organisms (rat, chick embryos), a comparison between human and non-human stem cells will be crucial in translating results from animal studies for stem cell-based therapies in humans.
BRIEF BACKGROUND
Stem cell (embryonic and adult) biology and developmental biology are at stages that offer exciting new research opportunities. Exploration of these opportunities is now possible with the release of the NIH guidelines for human embryonic stem cell research and the availability of human cell lines through the NIH registry.
Adult stem cells are present in many tissues of adult organisms and are important in tissue repair and homeostasis. Adult stem cells have the ability to self-renew (give rise to a replacement cell at each cell division with no apparent limitation) as well as generate another cell that is committed to differentiation in a particular tissue. Understanding the mechanisms of stem cell-renewal could provide fundamental insights not only into the origin of multicellular organisms, but also into regeneration of specific tissues and elucidation of complex events such as tumorigenesis, whereby a "cancer stem cell" with a similar capacity for self- renewal drives disease progression.
Embryonic stem cells (ES), that are derived from embryos at the blastocyst stage, may have a broader natural potential since, during development they normally produce all the cells of an organism. These pluripotent cells are characterized by nearly an unlimited self-renewal and differentiation capacity which can give rise to many differentiated cell types including neurons, glia, skeletal myocytes, adipocytes and haemopoietic cells. The main difference between the embryo-derived pluripotent cells and the so-called multipotent adult stem cells is in the number of differentiated cell types that they can produce. This may reflect the different origins of these cells; pluripotent stem cells are derived from blastocyst cells, while adult stem cells are derived from somatic cells that no longer possess the capacity to develop into the full spectrum of cell types. The stem and precursor cells can be used for examining mechanisms of progenitor cell differentiation and identifying environmental signals that are specific for cell maintenance, cell renewal and activation of differentiation pathways.
In order to take advantage of the new opportunities in human stem cell research the NIDCR wishes to issue an RFA to encourage research on the identification, purification and characterization of stem cell populations that give rise to orofacial tissues including teeth, salivary glands, oral epithelium, cartilage, bone and smooth muscles. The following are some examples of potential research areas:
- identification and characterization of the stem cell population(s), in terms of molecular markers and cell lineage in the oral, dental and craniofacial tissues and organs;
- design of conditions for maintenance, ex vivo, of cell populations that retain their pluripotency or their multipotency;
- use of stem cells to understand the genetic mechanisms that regulate development of orofacial structures, how tissues are maintained in health and how tissues are repaired or regenerated following trauma and disease;
- development of markers that distinguish stem and progenitor populations and gene profiles that characterize all stages of differentiation;
- understanding the mechanisms that regulate self-renewal of stem cells in the oral epithelium, salivary gland, tooth structures and other craniofacial structures (e.g., bone, cartilage, muscles and nerves);
- use of stem cell lines to identify the environmental cues and conditions that are required for a human embryonic stem cell to give rise to cells that make up the different tissues of the orofacial complex;
- identification of signals, signaling pathways components, and transcriptional factors that regulate the fate(s) of transplanted human stem cells and their derivatives;
- identification, characterization and reproduction of the microenvironment ("niches") of stem and progenitor cells;
- identification of the optimal type of stem cell or stem cell derivative for specific assays and cell therapy for orofacial diseases and disorders;
- use of animal model systems of oral, dental and craniofacial diseases and disorders for screening and comparing the functional capabilities of implanted human stem cells and their progeny.
The NIDCR is planning a workshop in order to assemble a group of experts in the field of stem cell biology to assist the NIDCR in initiating, planning, and executing research in Stem Cell-based Therapies for Orofacial Repair/Regeneration/Prevention. The Working Group will define the state-of-the-art regarding stem cell-based therapies, discuss the implications of that knowledge for research, and identify opportunities and obstacles to successfully exploit stem cell-based therapies for repairing or replacing damaged, diseased, or defective orofacial tissue with new, functional tissue. Furthermore, the Working Group will define pathways for preventing or correcting dental and craniofacial defects that are detected early in development.
CURRENT PORTFOLIO OVERVIEW
The NIDCR's extramural program supports a number of grants on the development of tooth structures, a few on salivary gland and oral epithelium development and even less grants on the identification and isolation of stem and/or progenitor cells in any of these and other orofacial tissues. Therefore, the NIDCR wishes to encourage and stimulate research initiatives that take advantage of recent opportunities in human embryonic and adult stem cell research in order to expand its programs to these areas of research. It is expected that the understanding of cell lineage and the identification of stem and progenitor cells will lead to the development of stem cell-based therapeutic strategies for orofacial tissue repair and regeneration.
SCIENTIFIC OPPORTUNITIES
In future years it will be important to capitalize on human embryonic and adult stem cell research. The NIH, with the release of guidelines for human embryonic stem cells and the registry of human embryonic cell lines has eliminated some of the hurdles in this area of research. The NIDCR is uniquely positioned to develop new initiatives that are specific to the tissues and organs of the orofacial complex.
COLLABORATIVE ACTIVITIES
The Officeof Research on Women's Health (ORWH) has expressed an interest in supporting this initiative.
FUNDING MECHANISMS
The issuanceof an RFA on "Stem Cell and Lineage Analysis of Orofacial Structures" is recommended. The funding mechanism will be the Exploratory/Developmental R21.
REFERENCES
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Donavon, P. J., and Gearhart, J. The end of the beginning for pluripotent stem cells. Nature 414, 118-121, 2001.
Fuchs, E., and Segre, J. A., Stem cells: a new lease on life. Cell 100, 143-155, 2000.
Ghazizadeh, S., and Taichman, L.B. Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO 20, 1215-1222, 2001.
Gronthos, S., Mankani, M., Gehron-Robey, P. and Shi, S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. PNAS 97, 13625-13630, 2000.
Reya, R., Morrison, S.J., Clarke, M. F., and Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 118-121, 2001.
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