Nathan Welham, PhD

Portrait of Nathan Welham, PhD
Associate Professor
K4/723 CSC
600 Highland Avenue
Madison, WI 53792
Focus Groups: 
PhD University of Wisconsin-Madison
BSLT, MSLT University of Canterbury
Research Summary: 
Vocal fold mucosal biology
Research Detail: 

Our work is focused on vocal fold mucosal biology. Vocal folds are uniquely housed at the boundary of the upper and lower airways and gastrointestinal tract, and are the only tissues in the human body that routinely oscillate at frequencies ranging from ~100-1000 Hz, in order to generate voice. Voice disorders influence around 5% of the United States population at any given time, cost the economy up to $20 billion per year in health care costs and occupational productivity loss, and so represent a meaningful medical, scientific and societal problem.

Fibrosis: Vocal fold injury resulting in scar formation is a recalcitrant clinical problem. Our group has worked on this problem for over a decade, with a particular focus on characterizing the role of migrating cells (e.g., bone marrow-derived progenitors, leukocyte subpopulations such as fibrocytes and macrophages) in the injury response. As part of this work, our group introduced a mouse surgical injury model, which has enabled the use of transgenic technologies in tackling this problem. We have examined re-epithelialization, the role of vitamin A-storing vocal fold stellate cells, and the therapeutic potential of biologics such as recombinant TGF-β3.

Stellate cells and retinoid biology: We are conducting work to better understand the function of vocal fold stellate cells. These cells, which are located in opposing anatomic niches (termed macula flavae) at the anterior and posterior boundaries of the vocal fold and store vitamin A, are claimed to hold critical functions in vocal fold mucosal development, extracellular matrix metabolism, and injury response, but to date have mostly been evaluated in descriptive studies. Our initial work, based on an assumption that vocal fold stellate cells are somewhat analogous to hepatic stellate cells, involved species comparisons to identify the most suitable in vivo model for subsequent studies and the development of a robust protocol to purify and culture human vocal fold stellate cells for in vitro studies. We are now using various retinol analogs to study vitamin A transport between liver and vocal fold mucosa, in a rat model and using human tissue/serum; comparing vocal fold stellate cell, vocal fold fibroblast, and hepatic stellate cell phenotypes; studying the importance of vocal fold stellate cells in mucosal development via transgenic knockout and genetic lineage tracing techniques; and modeling the stellate cell biomechanical environment using a computational approach.

Systems Biology: The vocal fold is an exquisite, purpose-specific biological system that facilitates voice production. Classic studies of the vocal fold mucosa and its underlying thyroarytenoid muscle have focused on individual or small groups of genes, proteins, and glycans, selected based on historical precedent and their importance in other systems. This work is useful, but does not reflect the vocal fold’s inherent biological complexity. In partnership with our collaborators, we have harnessed tools from systems biology to characterize the vocal fold at the transcriptomic and proteomic levels. This work is providing new insights in the areas of basic mucosal biology, muscle biology, wound healing, and tissue engineering.

Tissue Engineering: There are a number of preclinical and clinical approaches to treat impaired vocal fold mucosa; however, in cases of profound tissue impairment or loss, the best option may complete tissue replacement. Towards this goal, our group has been working on the development of a physiologically-appropriate engineered vocal fold mucosa for eventual clinical implantation. This engineered tissue is generated via 3D organotypic culture of primary human vocal fold mucosal cells in an acellular scaffold, and has shown significant promise in preclinical studies.

Selected Publications: 
Ling C, Yamashita M, Zhang J, Bless DM, Welham NV. Reactive response of fibrocytes to vocal fold mucosal injury in rat. Wound Repair Regen. 2010; 18: 514-523. PMCID: PMC3021622.
Chang Z, Ling C, Yamashita M, Welham NV. Microarray-driven validation of reference genes for quantitative real-time polymerase chain reaction in a rat vocal fold model of mucosal injury. Anal Biochem. 2010; 406: 214-221. PMCID: PMC2951325.
Ling C, Raasch JL, Welham NV. E-cadherin and transglutaminase-1 epithelial barrier restoration precedes type-IV collagen basement membrane reconstruction following vocal fold mucosal injury. Cells Tissues Organs. 2011; 193: 158-169. PMCID: PMC3064938.
Welham NV, Yamashita M, Choi SH, Ling C. Cross-sample validation provides enhanced proteome coverage in rat vocal fold mucosa. PLoS One. 2011; 6: e17754. PMCID: PMC3057991.
Welham NV, Chang Z, Smith LM, Frey BL. Proteomic analysis of a decellularized human vocal fold mucosa scaffold using 2D electrophoresis and high-resolution mass spectrometry. Biomaterials. 2013; 34: 669-676. PMCID: PMC3496020.
Chang Z, Kishimoto Y, Hasan A, Welham NV. TGF-β3 modulates the inflammatory environment and reduces scar formation following vocal fold mucosal injury in rats. Dis Model Mech. 2014; 7: 83-91. PMCID: PMC3882051.
Toya Y, Riabroy N, Davis CR, Kishimoto Y, Tanumihardjo SA, Bless DM, Welham NV. Interspecies comparison of stellate cell-containing macula flavae and vitamin A storage in vocal fold mucosa. J Anat. 2014; 225: 298-305. PMCID: PMC4166970.
Welham NV, Ling C, Dawson JA, Kendziorski C, Thibeault SL, Yamashita M. Microarray-based characterization of differential gene expression during vocal fold wound healing in rat. Dis Model Mech. 2015; 8: 311-321. PMCID: PMC4348567.
Ling C, Li Q, Brown ME, Kishimoto Y, Toya Y, Devine EE, Choi KO, Nishimoto K, Tsegyal T, Jiang JJ, Burlingham WJ, Gunasekaran S, Smith LM, Frey BL, Welham NV. Bioengineered vocal fold mucosa for voice restoration. Sci Transl Med. 2015; 7: 314ra187. PMCID: PMC4669060.
Li Q, Uygun BE, Geerts S, Ozer S, Scalf M, Giplin SE, Ott, HC, Yarmush ML, Smith LM, Welham NV, Frey BL. Proteomic analysis of naturally-sourced biological scaffolds. Biomaterials. 2016; 75: 37-46. PMCID: PMC4644483.