Stem Cell / Regenerative Medicine for Upper Airway Diseases 

Upper airway diseases of the nasal cavity and sinuses create significant morbidities and socioeconomic burdens. These include the many forms of chronic rhinosinusitis (CRS), which afflict 10% of the US population, the rare but debilitating breathing disorder termed empty nose syndrome (ENS, described under a different heading, and cystic fibrosis (CF), the #1 most lethal genetic disease in the world. diseases. 

We are using advanced cellular and molecular techniques, in murine and human systems, to better understand the mechanisms utilized by upper airway basal stem cells (ABCs) to maintain, repair and regenerate the upper airway epithelial barrier in both health and disease. is critical to improving available treatments for these common disease processes.  

Our laboratory has helped to pioneer early discoveries of mouse and human UABCs that are abundant, multipotent progenitors. We have studied ABCs using a variety of cell culture, flow cytometry, imaging, microarray and single cell molecular platforms to understand the biologic properties and unique signatures expressed by these cells.

We recently confirmed the direct involvement of ABCs in human upper airway tissue repair in patients undergoing sinus/skull base surgery. This was a randomized, blinded controlled trial undertaken at Stanford (Dr. Nayak and colleagues) and the University of Alabama Birmingham (Dr. Woodworth and colleagues), to understand whether use of a porcine tissue graft (termed pSIS) would promote/improve wound healing and tissue regeneration in the upper airway.  Our findings were that the pSIS significantly improved epithelial regeneration in the nasal airway, and that enhanced recruitment of ABCs into the wound healing tissue bed was present.  

Finally, we have advanced an exciting collaboration with 3 other laboratory groups at Stanford, to determine whether it is possible to efficiently perform genome correction of critical mutations that lead to cystic fibrosis at the stem cell level. With the Nayak lab group providing the human airway basal stem cells (ABCs) from cystic fibrosis and non-CF patients from surgery, the ABC stem cell numbers are then amplified in the organoid biology laboratory of Dr. Calvin Kuo, taken to the CRISPR gene editing laboratory of Dr. Matthew Porteus for CFTR mutational correction. After stem cell expansion and functional analysis/imaging in the laboratories of Drs. Tushar Desai and Zachary Sellers, the normalized/newly-corrected ABCs are returned to the Nayak Lab for cell embedding and transplantation experiments. The goal of this work is to design a novel, stem cell-based treatment for cystic fibrosis, and our advances to date are currently under review at the journal Cell Stem Cell. 

With our experimental foundation, we feel that airway basal stem cells represent a highly attractive cell therapy modality for treating a variety of upper (and possibly lower) airway disorders.

Publications

Vaidyanathan, Sriram, Ameen A. Salahudeen, Zachary M. Sellers, Dawn T. Bravo, Shannon S. Choi, Arpit Batish, Wei Le, et al. “High-Efficiency, Selection-Free Gene Repair in Airway Stem Cells from Cystic Fibrosis Patients Rescues CFTR Function in Differentiated Epithelia.” Cell Stem Cell 26, no. 2 (2020): 161-171.e4. https://doi.org/10.1016/j.stem.2019.11.002.
Cho, Kyu-Sup, Hee-Young Park, Hwan-Jung Roh, Dawn T. Bravo, Peter H. Hwang, and Jayakar V. Nayak. “Human Ethmoid Sinus Mucosa: A Promising Novel Tissue Source of Mesenchymal Progenitor Cells.” Stem Cell Research & Therapy 5, no. 1 (January 24, 2014): 15. https://doi.org/10.1186/scrt404.
Bravo, Dawn T., Ethan Soudry, Justin A. Edward, Wei Le, Alan L. Nguyen, Peter H. Hwang, Mrinmoy Sanyal, and Jayakar V. Nayak. “Characterization of Human Upper Airway Epithelial Progenitors.” International Forum of Allergy & Rhinology 3, no. 10 (October 2013): 841–47. https://doi.org/10.1002/alr.21205.