α₆β₄ Integrin Directs Alveolar Epithelial Migration

Integrins are transmembrane glycoproteins that play essential roles in variety of cellular behaviors including adhesion and motility. Each integrin is comprised of a heterodimeric pairing of α and β subunits that determine the specificity to various substrates, and the distribution of integrin expression is dictated by the cell type and the underlying function it must serve (1). In particular, α₆β₄ integrin expression is confined only to epithelia and has a major function as a cell adhesive molecule, particularly in the epidermis, where it is a constituent of the hemidesmosome (2). However, α₆β₄ integrin also regulates biological processes such as cell migration, invasion, and angiogenesis (3, 4). Although integrins facilitate cell motility by providing contact points by which the cell generates traction forces (i.e., focal adhesions), activation of intracellular signals are equally important in promoting cell migration (1).

In this issue of the Journal, Colburn and Jones (pp. 443–452), demonstrate the importance of α₆β₄ integrin in migration of the alveolar type II (ATII) cells (5). Using an array of cell biological techniques, the investigators convincingly show that the α₆β₄ integrin promotes processivity (directional migration) of individually migrating cells. Central to this effect is the ability of α₆β₄ integrin to activate Rac1, a small GTPase important in lamellipodial formation and directional migration (6). These studies replicate previous findings demonstrating that α₆β₄ integrin controls motility by regulating Rac1 signaling further solidifying these fundamental signaling pathways identified as important for epithelial cell migration (7, 8).

The α₆β₄ integrin effect on processivity appears to reflect as increased migration speed in collective migration of epithelial sheets potentially by properly aligning the cells to migrate toward the injury. Interestingly, these investigators find that α₆β₄ integrin expression and subsequent Rac1 activation is only required by leader cells to stimulate collective migration of the entire epithelial sheet, which is consistent with the leader–follower cell concept that has been corroborated in various forms of collective migration (6, 9). The significance of this findings is that only a small subset of alveolar epithelial cells at an injury front needs to express α₆β₄ integrin to stimulate collective migration of the entire epithelial sheet over a wounded area. Expression of α₆β₄ integrin is restricted to a select population of multipotent progenitor cells that can give rise to both airway and alveolar epithelium (10, 11). Therefore, under injury conditions, one possibility is that ATII cells at the wound edge induce α₆β₄ integrin expression to facilitate re-epithelialization. Alternatively, migration could be preferentially restricted to multipotent progenitor cells that move toward injured surfaces to stimulate repair and repopulation of the epithelial barrier. Thus, migration would be preferential in α₆β₄-expressing progenitor cells that are designed for lung repair, creating a ranking of reparative (migratory) cells that mirror the hierarchal structure of progenitor cells in the lungs (11).

ATII cells generally do not express α₆β₄ integrin (10, 11), which implies that the majority of alveolar epithelial cells are relatively stationary. However, these investigators show that forced overexpression of the β₄ subunit augments collective migration speed, reinforcing the notion that α₆β₄ integrin activates pro-migratory cellular signals (e.g., Rac1). Teleologically, there may be evolutional advantages for limiting α₆β₄ integrin expression, and thus migration, to a subset of cells. ATII cells are the tumor-initiating cells for adenocarcinoma, so having a pro-migratory phenotype may have nefarious consequences for the host (12). Indeed, malignant invasive and metastatic machinery often co-opt migratory signaling pathways (13). Furthermore, α₆β₄ integrin is up-regulated in lung cancer cells, and a high level of expression is a negative prognostic factor for patients with lung cancer (14). The majority of the data presented here is generated using A549 cells, an adenocarcinoma cell line, which could restrict the applicability of the results to malignancies. Tempering this limitation is the replication of these findings in primary ATII cells, and other published findings demonstrating α₆β₄ integrin promotes migration in nonmalignant keratinocytes (8, 15).

The studies by Coburn and colleagues do not specifically differentiate whether re-epithelialization of the alveolar surfaces is driven by re-expression of α₆β₄ integrin in ATII cells or migration of α₆β₄⁺ progenitor cells. Moreover, these are not necessarily mutually exclusive possibilities. The investigators do provide some data that may support the latter model. They demonstrate that primary ATII cells in cell culture, which in essence is a damaged situation (16), lack expression of α₆β₄ integrin. Therefore, this finding suggests ATII cells lack the ability to induce α₆β₄ integrin when injured and implies migration is predominantly limited to a pool of multipotent progenitors.

Much is still to be learned about how α₆β₄ integrin controls alveolar cell migration. For example, what are the signals that initiate the activation of Rac1 on injury. The data presented here are also limited in being performed only in cell culture, and future in vivo experiments using lineage-tracing techniques will be needed to fully elucidate the pertinence in context within our current understanding of lung regeneration. Nevertheless, the data support the concept that alveolar epithelial cells expressing α₆β₄ integrin in leader cells direct collective migration of the epithelium by activating Rac1.