Stem Cell Reports Article Sox10 Regulates Plasticity of Epithelial Progenitors toward Secretory Units of Exocrine Glands Harleen K. Athwal, 1,2,4 George Murphy III, 1,2,4 Ellis Tibbs, 3,4 Ashley Cornett, 1,2 Emily Hill, 1,2 Kenji Yeoh, 1,2 Elsa Berenstein, 3 Matthew P. Hoffman, 3 and Isabelle M.A. Lombaert 1,2,3, * 1 University of Michigan, Biointerfaces Institute, 2800 Plymouth Road, Ann Arbor, MI, USA 2 University of Michigan, School of Dentistry, Department of Biologic and Materials Sciences, 2800 Plymouth Road, Ann Arbor, MI 48109, USA 3 National Institutes of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA 4 Co-first author *Correspondence: lombaert@umich.edu https://doi.org/10.1016/j.stemcr.2019.01.002 SUMMARY Understanding how epithelial progenitors within exocrine glands establish specific cell lineages and form complex functional secretory units is vital for organ regeneration. Here we identify the transcription factor Sox10 as essential for both the maintenance and differentiation of epithelial KIT + FGFR2b + progenitors into secretory units, containing acinar, myoepithelial, and intercalated duct cells. The KIT/FGFR2b- Sox10 axis marks the earliest multi-potent and tissue-specific progenitors of exocrine glands. Genetic deletion of epithelial Sox10 leads to loss of secretory units, which reduces organ size and function, but the ductal tree is retained. Intriguingly, the remaining duct progenitors do not compensate for loss of Sox10 and lack plasticity to properly form secretory units. However, overexpression of Sox10 in these ductal progen- itors enhances their plasticity toward KIT + progenitors and induces differentiation into secretory units. Therefore, Sox10 controls plasticity and multi-potency of epithelial KIT + cells in secretory organs, such as mammary, lacrimal, and salivary glands. INTRODUCTION Cellular plasticity is an important feature within adult or- gans facilitating rapid adaptation of progenitors to injury or environmental changes. Previously, it was thought that progenitors within organs would respond to injury in a uni-directional cell lineage manner. A series of differen- tiation steps producing multiple cell intermediates, each with a more restricted lineage potential than the last, would eventually lead to specialized cells. Recent reports challenge this paradigm showing that cells can ac- quire characteristics of other cell types beyond their pro- posed lineage (Tata and Rajagopal, 2016) by converting into earlier cell types (de-differentiation), more distant phenotypes (trans-differentiation), or interchange be- tween different progenitors (trans-determination). Each of these three cellular processes may occur in different set- tings and to various degrees (Donati and Watt, 2015). Inter- estingly, both cell-autonomous and non-cell-autonomous mechanisms are proposed to contribute to this plasticity. Environmental factors, such as cell-cell contact or ligand presentation, contribute to non-cell-autonomous induc- tion. Whereas transcription factors (TFs) are part of the autonomous mechanism, playing a major role in regu- lating cell fate, stability, and conversion. However, very lit- tle is known about how plasticity is regulated, and how it varies among cell types and different conditions. Exocrine glands, such as the mammary, lacrimal, and salivary glands, all share a similar secretory function that entails production and secretion of milk, tears, and saliva, respectively (Wang and Laurie, 2004). They all undergo branching morphogenesis to create a ductal tree structure distally ending in secretory units whereby fluid can be pro- duced, modified, transported, and released from the gland. These secretory units include secretory acinar cells, associ- ated intercalated ducts that connect larger ducts to the acini, and contractile myoepithelial cells surrounding the acini (Lombaert et al., 2017). As such, it was postulated that various signaling pathways and cellular mechanisms must overlap among these exocrine glands (Wang and Laurie, 2004). For example, the TF MIST1 was identified as a ‘‘scaling factor’’ to induce and maintain the secretory cell architecture of mature acinar cells in multiple exocrine tissues (Lo et al., 2017). However, which specific TFs con- trol and direct epithelial progenitors to form the secretory units, and whether common TFs are involved in different organs are unknown. TFs whose activity is necessary and sufficient to direct specific cell lineage commitment, and that can also re- specify the fate of cells destined to become other lineages, are termed core master regulators (Chan and Kyba, 2013). Master regulators promote gene transcription to initiate or maintain the desired cell fate, and repress gene expres- sion that oppose this decision; ultimately stabilizing cell fate decisions. Here we identify Sox10 as a master regulator to maintain and direct KIT + progenitors into secretory units of exocrine glands. SOX proteins have previously been described as mediators of both stemness and cell differenti- ation (Abdelalim et al., 2014), and Sox10 is well-known for its role in neural crest stem cell maintenance and their differentiation into oligodendrocytes and glia cells (Rei- prich and Wegner, 2015). Surprisingly, more recent studies 366 Stem Cell Reports j Vol. 12 j 366–380 j February 12, 2019 j ª 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).