Tissue Engineering and Regenerative Medicine Program
Integrative Biology and Infectious Diseases Branch
Division of Extramural ResearchBack to top
Regenerative medicine strives to heal and functionally and structurally restore tissues and organs compromised by disease or injury. Significant advances are continually being made in this area; however, one of the remaining bottlenecks impeding progress has been accessibility of cell sources for generation of new tissues. Currently available methods often rely on injection into tissues of in vitro expanded heterogeneous multipotent stem and progenitor cell populations or of in vitro differentiated progeny of pluripotent cell lines. While there have been promising developments in this area, many challenges remain, including insufficient characterization of stem/progenitor cell sources as to their capacity to generate functional differentiated cell progeny, which results in insufficient numbers of cells available for building new tissues and poor survival and integration of injected cells with the host tissues. The present Initiative is geared toward addressing these obstacles, as they apply to healing and regeneration of dental, oral and craniofacial (DOC) tissues. Specifically, its goal is to interrogate the capacity of cells residing in the postnatal DOC tissues to acquire developmental plasticity to undergo lineage reprogramming (trans-differentiation) in vivo in response to injury and other types of environmental stress, and to generate functionally-competent cells of alternative lineage(s). The end goal of this initiative is to develop approaches for capitalizing on this developmental plasticity for obtaining needed cell sources. This Initiative will build a basic science foundation for developing clinically-relevant minimally-invasive strategies for overcoming limitations of the currently available regenerative medicine methodologies.Back to top
The capacity of DOC tissues to undergo endogenous healing and regeneration remains largely unexplored. It varies widely among species, types of DOC tissues, and the extent of incurred injury. For example, following cuts and abrasions, normal human oral mucosa heals better and faster than most other tissues in the body. On the other hand, oral cancer chemotherapy and radiation commonly result in nonhealing lesions of oral mucosa oral mucositis – a condition responsible for severe morbidity in patients. Human dental and salivary gland tissues do not exhibit significant regenerative capacity, while rodent incisors regenerate throughout life. Human craniofacial bone and skeletal muscle regenerate small defects but fail to do so when the defect exceeds critical size. While mechanisms of differential regenerative capacity of tissues are complex and still poorly understood, it is recognized that the availability of stem/progenitor cells to generate new tissue is one of the key factors needed for successful regeneration. Traditionally, in mammals the developmental progression from stem/progenitor cells to fully-differentiated cells have been viewed as a unidirectional and terminal process, but recent advances beginning with the discovery of cellular reprogramming and derivation of induced pluripotent stem cells, put the universality of this simple paradigm into question. In fact, multiple examples of naturally-occurring in vivo reprogramming of differentiated cells into stem/progenitor state following injury and/or inflammatory stress have been described. The best-studied example of this phenomenon is found in mammalian small intestine, but similar findings have been described in the lung, skin, pancreas, liver, brain and heart. Alternatively, and/or in addition, lineage reprogramming in vivo can be induced by targeted gene transfer to deliver to cells genes coding for master tissue-specific genetic and epigenetic regulators via viral vectors or other gene transfer technologies. Accomplishing controlled and safe in vivo lineage reprogramming would provide minimally-invasive means for generating needed cell sources. Moreover, such reprogrammed cells are likely to have multiple advantages over injected in vitro-manipulated cells, because survival, function and integration of in vivo reprogrammed cells with host tissues would be supported by endogenous DOC stem cells niches. In these niches, accessory somatic cells, soluble signaling mediators and extracellular matrices would provide guidance cues to stem/progenitor cells to generate new tissues. Overall, achieving the goals of this initiative will create unprecedented opportunities for healing and regeneration of DOC tissues.Back to top
Gaps and Opportunities
Significant knowledge gaps currently exist in understanding of inherent and induced lineage plasticity of mammalian DOC tissues and role of stem cells niches and other signals, including immune system-mediated signals, in controlling this plasticity. Overcoming these knowledge gaps is likely to create a new generation of approaches - autotherapies - that take advantage of endogenous healing and regeneration capacity of DOC tissues to restore their structure and function. More specifically, these autotherapies will target endogenous DOC stem/progenitor cell niches and differentiated somatic cells for lineage reprogramming for deriving new cell sources to re-build DOC tissues and restore normal tissue homeostasis. New opportunities to interrogate the existing knowledge gaps are offered by recent advances in several fields, including, single cell-based analyses, tissue organoids and tissue/organ on chips technologies, advanced genome-editing and gene transfer technologies, high-resolution real-time imaging modalities, systems biology and bioinformatics, among others. Currently, NIDCR portfolio does not contain projects directly focusing on in vivo lineage reprogramming. However, several NIDCR-supported investigators already have promising preliminary and published results suggestive of inherent lineage plasticity of DOC tissues. Several NIH Institutes including NIDDK, NIAMS, NHLBI and NINDS, currently support such projects as applied to those Institutes missions. The proposed NIDCR initiative is synergistic with this existing effort. Moreover, a Keystone Symposium titled “Cellular Plasticity: Reprogramming, Regeneration and Metaplasia”, was held in January 2019, indicative of a robust interest of the scientific community, and of a critical mass of knowledge being generated in this emerging field. Given the strong interest of NIDCR in advancing DOC tissue regeneration, it is important for the Institute to join this trans-NIH effort. To achieve maximum results, this initiative will highly encourage collaborations of DOC tissue regeneration experts with investigators exploring lineage plasticity and reprogramming of other tissues in the body.Back to top
Scientific Areas of Interest
A long-term goal of this Initiative within the umbrella of NIDCR 2030 Theme Autotherapies, is to develop practical approaches for generation of abundant supply of high-quality cell sources for regeneration of DOC tissues from the endogenous tissue-resident cells. However, before translational strategies could be developed to achieve this goal, it will be necessary to build a strong basic science knowledge base to define the capacity of cells in different DOC tissues to undergo in vivo lineage reprogramming, elucidate molecular and cellular mechanisms, identify signaling pathways and mediators of this reprogramming, and develop approaches for optimizing safety and efficiency of reprogramming in appropriate animal models. While the focus of this initiative is lineage reprogramming in vivo, employment of in vitro model systems, such as tissue chip and organoid cultures would be within the scope of this initiative, as long as the proposed experimental plan addresses questions relevant to reprogramming in vivo.Back to top
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