title: Effects of Human Mesenchymal Stem Cells Coculture on Calcium-Induced Differentiation of Normal Human Keratinocytes.
abstract: The influence of mesenchymal stem cells (MSCs) on keratinocytes in altered microenvironments is poorly understood. Here, we cocultured umbilical cord blood-derived MSCs with normal human epidermal keratinocytes to evaluate their paracrine effect in the presence of high extracellular calcium (Ca2+) concentration. High Ca2+environment to keratinocytes can disrupt normal skin barrier function due to abnormal/premature differentiation of keratinocytes. Surprisingly, we found that MSCs suppress both proliferation and differentiation of keratinocytes under a high Ca2+environment in transforming growth factors β1 (TGFβ1)-dependent manner. Furthermore, we determined that MSCs can regulate the mitogen-activated protein kinases, phosphatidylinositol 3-kinase/protein kinase B, and protein kinase C pathways in Ca2+-induced differentiated keratinocytes. Knockdown of TGFβ1 from MSCs results in decreased suppression of differentiation with significantly increased proliferation of keratinocytes compared with control MSCs. MSCs-derived TGFβ1 further induced growth inhibition of keratinocyte in high extracellular Ca2+environment as analyzed by a decrease in DNA synthesis, accumulation of phosphorylated retinoblastoma protein, cdc2, and increased mRNA level of p21, and independent of TGFβ1/SMAD pathway. Taken together, we found that MSCs-derived TGFβ1 is a critical regulator of keratinocyte function, and involves multiple proximal signaling cascades. Stem Cells 2017;35:1592-1602.
authors.affiliation: Laboratory of Dermatology-Immunology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Shyam Kishor
authors.initials: SK
authors.lastname: Sah
authors.affiliation: Laboratory of Dermatology-Immunology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Department of Dermatology, The Catholic University of Korea, St. Vincent's Hospital, Jungbu-daero, Paldal-gu, Suwon-si, Gyeonggi-do, Republic of Korea.
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Integrated Life Sciences, Dankook University, Jukjeon-ro, Suji-gu, Yongin, Republic of Korea.
authors.forename: Seong-Wook
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute, Pusan National University, School of Medicine, Pusan National University Hospital, Busan, Republic of Korea.
authors.forename: Hyung-Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Graduate School of New Drug Development, Chungnam National University, Republic of Korea.
authors.forename: Yeon-Soo
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Kang
authors.affiliation: Laboratory of Dermatology-Immunology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Tae-Yoon
authors.identifier: 0000-0001-9843-0356
authors.initials: TY
authors.lastname: Kim
mesh_terms: D002118:Calcium / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods*; D005110:Extracellular Space / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D008565:Membrane Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C064554:loricrin; D007633:Keratins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium
keywords: Differentiation; Keratinocytes; Mesenchymal stem cells