Our long-term goal is to produce a """"""""smart"""""""" transduced oral mucosal graft that will be used for reconstruction of major oral defects. Currently, an unfractionated unsorted human adult single keratinocyte suspension is used to manufacture a """"""""naive"""""""" non-transduced Ex Vivo Produced Oral Mucosa Equivalent (EVPOME) that is suitable to perform FDA-approved human clinical trials. Our success with fractionated unsorted cultured adult human oral mucosal cells provides compelling empiric evidence that a subpopulation exists within our cell population that represents the """"""""stem"""""""" cell compartment. In order for our technology/gene therapy to become a clinically viable option we need to isolate a progenitor/stem cell population. Our hypothesis states: """"""""A subpopulation of fractionated sorted oral mucosa keratinocytes enriched for progenitor/stem cells can be: 1) isolated and 2) manipulated to alter their replication and differentiation, to enhance their ability to fabricate a superior EVPOME graft for intraoral grafting and for use as a device for gene therapy.
Specific Aims : 1. Isolate and characterize an """"""""enriched population"""""""" of oral mucosa progenitor/stem cells from fractionated sorted cultured primary human oral keratinocytes. 2. Demonstrate the safety and fate of a transduced enriched population of oral mucosa progenitor/stem cells in a """"""""smart"""""""" EVPOME by grafting into both SCID mouse and canine models. 3. Alter expression of nuclear transcription factor PPARy to enhance replication and decrease differentiation of an enriched population of oral mucosa progenitor/stem cells. This research project is a logical and necessary iteration of the """"""""bench to bedside"""""""" paradigm as it applies to the EVPOME. The results to establish expanded cultures of an enriched population of oral mucosa progenitor/stem cells, under chemically defined conditions and FDA guidelines, can lead to greater advances in cell replacement therapy. These types of translational studies are needed to generate new cell based tissue-engineered devices to improve patient care.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Lumelsky, Nadya L
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Winterroth, Frank; Kato, Hiroko; Kuo, Shiuhyang et al. (2014) High-frequency ultrasonic imaging of growth and development in manufactured engineered oral mucosal tissue surfaces. Ultrasound Med Biol 40:2244-51
Winterroth, Frank; Hollman, Kyle W; Kuo, Shiuhyang et al. (2013) Characterizing morphology and nonlinear elastic properties of normal and thermally stressed engineered oral mucosal tissues using scanning acoustic microscopy. Tissue Eng Part C Methods 19:345-51
Izumi, Kenji; Neiva, Rodrigo F; Feinberg, Stephen E (2013) Intraoral grafting of tissue-engineered human oral mucosa. Int J Oral Maxillofac Implants 28:e295-303
Izumi, Kenji; Marcelo, Cynthia L; Feinberg, Stephen E (2013) Enrichment of oral mucosa and skin keratinocyte progenitor/stem cells. Methods Mol Biol 989:293-303
Marcelo, Cynthia Luz; Peramo, Antonio; Ambati, Amala et al. (2012) Characterization of a unique technique for culturing primary adult human epithelial progenitor/""stem cells"". BMC Dermatol 12:8
Peramo, Antonio; Marcelo, Cynthia L; Feinberg, Stephen E (2012) Tissue engineering of lips and muco-cutaneous junctions: in vitro development of tissue engineered constructs of oral mucosa and skin for lip reconstruction. Tissue Eng Part C Methods 18:273-82
Winterroth, Frank; Hollman, Kyle W; Kuo, Shiuhyang et al. (2011) Comparison of scanning acoustic microscopy and histology images in characterizing surface irregularities among engineered human oral mucosal tissues. Ultrasound Med Biol 37:1734-42
Winterroth, Frank; Lee, Junho; Kuo, Shiuhyang et al. (2011) Acoustic microscopy analyses to determine good vs. failed tissue engineered oral mucosa under normal or thermally stressed culture conditions. Ann Biomed Eng 39:44-52
Winterroth, Frank; Hollister, Scott J; Feinberg, Stephen E et al. (2011) Non-linear stress-strain measurements of ex vivo produced oral mucosal equivalent (EVPOME) compared to normal oral mucosal and skin tissue. Conf Proc IEEE Eng Med Biol Soc 2011:286-9
Tobita, T; Izumi, K; Feinberg, S E (2010) Development of an in vitro model for radiation-induced effects on oral keratinocytes. Int J Oral Maxillofac Surg 39:364-70

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