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† Author contributions: G.S.L.T.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; J.A.A. And R.M.: conception and design, collection and/or assembly of data, and data analysis and interpretation; S.E.B. And K.S.: collection and/or assembly of data; T.E.S.: collection and/or assembly of data and data analysis and interpretation; A.M.D.: data analysis and interpretation; J.M.K.: conception and design, financial support, data analysis and interpretation, and manuscript writing; C.V.C.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript. Systemically administered adult mesenchymal stem cells (MSCs), which are being explored in clinical trials to treat inflammatory disease, exhibit the critical ability to extravasate at sites of inflammation.

Kouki Ichinose ( 一の瀬後期, Ichinose Kōki) Voiced by: (Japanese); (English) A confectioner that works in the shop where Rinko works for a part-time job. He falls in love upon seeing Rinko and considers her his muse. Unlike the other girls rejected by Suna, Suna felt bad and guilty for seeing her cry.

We aimed to characterize the basic cellular processes mediating this extravasation and compare them to those involved in leukocyte transmigration. Using high‐resolution confocal and dynamic microscopy, we show that, like leukocytes, human bone marrow‐derived MSC preferentially adhere to and migrate across tumor necrosis factor‐α‐activated endothelium in a vascular cell adhesion molecule‐1 (VCAM‐1) and G‐protein‐coupled receptor signaling‐dependent manner. As several studies have suggested, we observed that a fraction of MSC was integrated into endothelium. In addition, we observed two modes of transmigration not previously observed for MSC: Paracellular (between endothelial cells) and transcellular (directly through individual endothelial cells) diapedesis through discrete gaps and pores in the endothelial monolayer, in association with VCAM‐1‐enriched “transmigratory cups”.

Contrasting leukocytes, MSC transmigration was not preceded by significant lateral migration and occurred on the time scale of hours rather than minutes. Interestingly, rather than lamellipodia and invadosomes, MSC exhibited nonapoptotic membrane blebbing activity that was similar to activities previously described for metastatic tumor and embryonic germ cells. Our studies suggest that low avidity binding between endothelium and MSC may grant a permissive environment for MSC blebbing. MSC blebbing was associated with early stages of transmigration, in which blebs could exert forces on underlying endothelial cells indicating potential functioning in breaching the endothelium.

Collectively, our data suggest that MSC transmigrate actively into inflamed tissues via both leukocyte‐like and novel mechanisms. S TEM C ELLS 20–2486.