SUMMARY The extent of lung regeneration following catastrophic damage and the potential role of adult stem cells in such a process remains obscure. Sublethal infection of mice with an H1N1 influenza virus related to that of the 1918 pandemic triggers massive airway damage followed by apparent regeneration. We show here that p63-expressing stem cells in the bronchiolar epithelium undergo rapid proliferation after infection and radiate to interbronchiolar regions of alveolar ablation. Once there, these cells assemble into discrete, Krt5+ pods and initiate expression of markers typical of alveoli. Gene expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network eradicated by viral infection. The dynamics of this p63-expressing stem cell in lung regeneration mirrors our parallel finding that defined pedigrees of human distal airway stem cells assemble alveoli-like structures in vitro and suggests new therapeutic avenues to acute and chronic airway disease.

SUMMARY Barrett's esophagus is an intestine-like metaplasia and precursor of esophageal adenocarcinoma. Triggered by gastroesophageal reflux disease, the origin of this metaplasia remains unknown. p63-deficient mice, which lack squamous epithelia, may model acid-reflux damage. We show here that p63 null embryos rapidly develop intestine-like metaplasia with gene expression profiles similar to Barrett's metaplasia. We track its source to a unique embryonic epithelium that is normally undermined and replaced by p63-expressing cells. Significantly, we show that a discrete population of these embryonic cells persists in adult mice and humans at the squamocolumnar junction, the source of Barrett's metaplasia. Upon programmed damage to the squamous epithelium, we show that these embryonic cells migrate towards adjacent, specialized squamous cells in a process that may recapitulate early Barrett's. Our findings suggest that certain precancerous lesions, such as Barrett's, initiate not from genetic alterations but from competitive interactions between cell lineages driven by opportunity.

The chemokine CXCL12 and the receptor CXCR4 play pivotal roles in normal vascular and neuronal development, in inflammatory responses, and in infectious diseases and cancer. For instance, CXCL12 has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation, whereas its receptor CXCR4 is involved in human immunodeficiency virus infection, cancer metastasis and in the rare disease known as the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. As we screened chemical libraries to find inhibitors of the interaction between CXCL12 and the receptor CXCR4, we identified synthetic compounds from the family of chalcones that reduce binding of CXCL12 to CXCR4, inhibit calcium responses mediated by the receptor, and prevent CXCR4 internalization in response to CXCL12. We found that the chemical compounds display an original mechanism of action as they bind to the chemokine but not to CXCR4. The highest affinity molecule blocked chemotaxis of human peripheral blood lymphocytes ex vivo. It was also active in vivo in a mouse model of allergic eosinophilic airway inflammation in which we detected inhibition of the inflammatory infiltrate. The compound showed selectivity for CXCL12 and not for CCL5 and CXCL8 chemokines and blocked CXCL12 binding to its second receptor, CXCR7. By analogy to the effect of neutralizing antibodies, this molecule behaves as a small organic neutralizing compound that may prove to have valuable pharmacological and therapeutic potential.Chemokines are small (8 -10-kDa) secreted proteins that play roles in the normal physiology of the immune system as well as in orchestrating leukocyte recruitment and activation in the context of inflammatory and infectious diseases (1). Most of them belong to one of two major subfamilies: the ␤ or CC chemokines in which two conserved cysteines from the amino terminus are adjacent to each other and the ␣ or CXC chemokines in which these two cysteines are separated by one residue. Chemokine receptors are members of the superfamily of G proteincoupled receptors characterized by seven transmembranespanning regions and coupling to heterotrimeric G proteins.The CXC chemokine stromal cell-derived factor-1 (SDF1), 5 now named CXCL12, binds to and activates the chemokine receptor CXCR4 as well as the more recently identified CXCR7 receptor (19). CXCL12 stimulates a rapid receptor-mediated intracellular calcium mobilization and signaling through a Pertussis toxin-sensitive G i protein. The response to CXCL12 and expression of the CXCR4 receptor occur at a very early stage of embryonic development and appear to be widely used whenever cell migration is required (2). Indeed mice lacking either CXCL12 or CXCR4 die prenatally and exhibit defects in vascular development, neuronal development, hematopoiesis, and cardiogenesis (3-6).Besides the regulation of homeostatic processes, the CXCR4 receptor is implicated in tumor metastasis (7) as well as in infectious and inflammatory diseases....