Ahmad Nabhan

Ahmad Nabhan

Assistant Professor of Cell Biology, Development and Physiology

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Research Interests

Communication between stem cells and their niche (stem-niche) is foundational for the collective cellular behavior of tissue repair and regeneration. The variable capacity to repair organs across different species is often dictated by differential stem-niche communication, highlighting the vast potential of modulating this cellular crosstalk towards regenerative therapies. However, the failure of clinical trials broadly modulating stem-niche signaling pathways such as Wnt and Tgf-B due to pleiotropy-associated toxicity underscores the need for new paradigms in understanding and manipulating stem-niche signaling. Our lab’s central focus is on molecularly decoding stem-niche communication to better understand tissue maintenance and, ultimately, to reprogram this crosstalk for precision therapies that enhance organ repair.

We use the lung alveolar stem cell and its interaction with its stromal niche as a model to study these broad questions. Alveolar stem cells are amongst the most dangerous cells in the body and disruption of their stem cell function underlies lung adenocarcinoma, the most frequent type of lung cancer. We have developed methods to genetically engineer primary alveolar stem cells and/or their niche then recreate their in vivo interactions ex vivo. This enables a high throughput, yet physiologically relevant dissection of their communication and how this crosstalk influences downstream processes such as stem cell proliferation, differentiation and surfactant production.

Current Projects

  1. What Are the Ligands, Receptors and Transcription Factors Controlling AT2 Differentiation? Differentiation of AT2 cells into flat, thin AT1 cells is fundamental to the lung’s gas exchange capacity, yet this process remains poorly understood. Additionally, how AT1 cells achieve the correct cellular morphology and "thinness" to allow passive gas diffusion is virtually unexplored. We are addressing these questions by combining single-cell RNA sequencing with high-throughput genetics to identify the genetic factors required for this process.
  2. How Do Stem Cells Shape Their Niche? While most studies focus on the signals stem cells receive from their niche, stem cells also send critical signals that shape niche cell behavior, particularly during development and in disease states such as fibrosis or within the tumor microenvironment. Exploring stem-to-niche signaling requires manipulating defined cell types and analyzing their effects on neighboring populations. Current tools are not suited to this task: Animal models are limited by low throughput as well as cellular complexity. Pooled genetic screens only predict potential up/down regulation of signaling ligands. We have developed genetic organoid screening platforms that allow us to study cellular communication at its most fundamental level—the interaction between two cell populations.

Selected Publications

Nabhan, A.N.#, Webster, J.D., Adams, J., Blazer, L., Everrett, C., Eidenschenk C., Arlantico, A., Brightbill, H.D., Wolters, P.J., Seshagiri, S., Angers, S., Sidhu, S.S., Newton, K., Arron, J.R., Dixit, V.M. # (2023). Targeted alveolar regeneration with Frizzled-specific agonists. Cell 186(14), 2995–3012.  
     # Corresponding authors
    Highlighted: T. Villanueva (2023) Selective activation of Wnt ameliorates idiopathic pulmonary fibrosis. Nat. rev. Drug Disc.

Travaglini, K.J.*, Nabhan, A.N.*, Penland, L., Sinha, R., Gillich, A., Sit, R.V., Chang, S., Conley, S.D., Mori, Y., Seita, J., Berry, J.B., Shrager, R.J., Metzger, C.S., Kuo, N., Neff, Weissman I.L., Quake S.R., Krasnow M.A. (2020). A molecular cell atlas of the human lung from single cell RNA sequencing. Nature, 587(7835), 619-625.
    * These authors contributed equally
    Highlighted: H. Stowers (2020) A map of lung cell types. Nat Med 27, 21. 

Nabhan, A. N., Brownfield, D. G., Harbury, P. B., Krasnow, M. A., Desai, T. J. (2018). Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells. Science, 359(6380), 1118-1123.
    Highlighted: B.L. Hogan (2018) Stemming Lung Disease? NEJM 378, 2439-2440. 
    Recommended: S. Yoshida. and T. Nakagawa (2018) F1000prime

Tabula Muris Consortium (2020). A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature, 583, 590–595.

Hansen, S., Zhang, Y., Hwang, S., Nabhan, A. N., Li, W., Fuhrmann, J., Kschonsak, Y., Zhou, L., Nile, A.H., Gao, X., Piskol R., de Sousa e Melo, F., de Sauvage F., and Hannoush R.N. (2022). Directed evolution identifies high-affinity cystine-knot peptide agonists and antagonists of Wnt/β-catenin signaling. PNAS, 119 (46) e2207327119.

Muus, C., Luecken, M. D., Eraslan, G., …Nabhan A.N., …Ziegler C., Human Cell Atlas Lung Biological Network (2021). Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nature Medicine, 27 (3), 546–559.

Tabula Muris Consortium (2018). Transcriptomic characterization of 20 organs and tissues from mouse at single cell resolution creates a Tabula Muris. Nature, 562, 367–372.
Led the team isolating and analyzing kidney, lung and spleen.

Ben-Shahar, O. M., Szumlinski, K. K., Lominac, K. D., Cohen, A., Gordon, E., Ploense, K. L., DeMartini, J., Bernstein, N., Rudy, N. M., Nabhan, A. N., Sacramento, A., Pagano, K., Carosso, G. A., & Woodward, N. (2012). Extended access to cocaine self-administration results in reduced glutamate function within the medial prefrontal cortex. Addiction Biology, 17, 746-757.

Last Updated 2024-10-14