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LL-37 stimulates the functions of adipose-derived stromal/stem cells via early growth response 1 and the MAPK pathway.
Stem Cell Res Ther. 2016 Apr 19; 7(1):58.SC

Abstract

BACKGROUND

LL-37 is a naturally occurring antimicrobial peptide found in the wound bed and assists wound repair. No published study has characterized the role of LL-37 in the function(s) of human mesenchymal stem cells (MSCs). This study investigated the functions of adipose-derived stromal/stem cells (ASCs) activated by LL-37 by performing both in vitro assays with cultured cells and in vivo assays with C57BL/6 mice with hair loss.

METHODS

Human ASCs were isolated from healthy donors with written informed consent. To examine the effects of LL-37 on ASC function, cell proliferation and migration were measured by a cell counting kit (CCK-8) and a Transwell migration assay. Early growth response 1 (EGR1) mRNA expression was determined by microarray and real-time PCR analyses. The protein levels of EGR1 and regenerative factors were analyzed by specific enzyme-linked immunosorbent assays and western blotting.

RESULTS

LL-37 treatment enhanced the proliferation and migration of human ASCs expressing formyl peptide receptor like-1. Microarray and real-time PCR data showed that EGR1 expression was rapidly and significantly increased by LL-37 treatment. LL-37 treatment also enhanced the production of EGR1. Moreover, small interfering RNA-mediated knockdown of EGR1 inhibited LL-37-enhanced ASC proliferation and migration. Activation of mitogen-activated protein kinases (MAPKs) was essential not only for LL-37-enhanced ASC proliferation and migration but also EGR1 expression; treatment with a specific inhibitor of extracellular signal-regulated kinase, p38, or c-Jun N-terminal kinase blocked the stimulatory effect of LL-37. EGR1 has a strong paracrine capability and can influence angiogenic factors in ASCs; therefore, we evaluated the secretion levels of vascular endothelial growth factor, thymosin beta-4, monocyte chemoattractant protein-1, and stromal cell-derived factor-1. LL-37 treatment increased the secretion of these regenerative factors. Moreover, treatment with the conditioned medium of ASCs pre-activated with LL-37 strongly promoted hair growth in vivo.

CONCLUSIONS

These findings show that LL-37 increases EGR1 expression and MAPK activation, and that preconditioning of ASCs with LL-37 has a strong potential to promote hair growth in vivo. This study correlates LL-37 with MSC functions (specifically those of ASCs), including cell expansion, cell migration, and paracrine actions, which may be useful in terms of implantation for tissue regeneration.

Authors+Show Affiliations

Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.Department of Life Science, Sookmyung Women's University, Seoul, Korea. cdhkor@sookmyung.ac.kr.Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. si55.bang@samsung.com. Bio-Med Translational Research Center, Samsung Medical Center, Seoul, Korea. si55.bang@samsung.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27095351

Citation

Yang, Yoolhee, et al. "LL-37 Stimulates the Functions of Adipose-derived Stromal/stem Cells Via Early Growth Response 1 and the MAPK Pathway." Stem Cell Research & Therapy, vol. 7, no. 1, 2016, p. 58.
Yang Y, Choi H, Seon M, et al. LL-37 stimulates the functions of adipose-derived stromal/stem cells via early growth response 1 and the MAPK pathway. Stem Cell Res Ther. 2016;7(1):58.
Yang, Y., Choi, H., Seon, M., Cho, D., & Bang, S. I. (2016). LL-37 stimulates the functions of adipose-derived stromal/stem cells via early growth response 1 and the MAPK pathway. Stem Cell Research & Therapy, 7(1), 58. https://doi.org/10.1186/s13287-016-0313-4
Yang Y, et al. LL-37 Stimulates the Functions of Adipose-derived Stromal/stem Cells Via Early Growth Response 1 and the MAPK Pathway. Stem Cell Res Ther. 2016 Apr 19;7(1):58. PubMed PMID: 27095351.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - LL-37 stimulates the functions of adipose-derived stromal/stem cells via early growth response 1 and the MAPK pathway. AU - Yang,Yoolhee, AU - Choi,Hyunju, AU - Seon,Mira, AU - Cho,Daeho, AU - Bang,Sa Ik, Y1 - 2016/04/19/ PY - 2015/10/14/received PY - 2016/04/04/accepted PY - 2016/03/21/revised PY - 2016/4/21/entrez PY - 2016/4/21/pubmed PY - 2016/12/15/medline KW - Adipose-derived stromal/stem cells KW - Cell migration KW - Early growth response 1 KW - Hair growth KW - LL-37 KW - MAPK pathway KW - Mesenchymal stem cells KW - Paracrine actions KW - Proliferation KW - Regeneration SP - 58 EP - 58 JF - Stem cell research & therapy JO - Stem Cell Res Ther VL - 7 IS - 1 N2 - BACKGROUND: LL-37 is a naturally occurring antimicrobial peptide found in the wound bed and assists wound repair. No published study has characterized the role of LL-37 in the function(s) of human mesenchymal stem cells (MSCs). This study investigated the functions of adipose-derived stromal/stem cells (ASCs) activated by LL-37 by performing both in vitro assays with cultured cells and in vivo assays with C57BL/6 mice with hair loss. METHODS: Human ASCs were isolated from healthy donors with written informed consent. To examine the effects of LL-37 on ASC function, cell proliferation and migration were measured by a cell counting kit (CCK-8) and a Transwell migration assay. Early growth response 1 (EGR1) mRNA expression was determined by microarray and real-time PCR analyses. The protein levels of EGR1 and regenerative factors were analyzed by specific enzyme-linked immunosorbent assays and western blotting. RESULTS: LL-37 treatment enhanced the proliferation and migration of human ASCs expressing formyl peptide receptor like-1. Microarray and real-time PCR data showed that EGR1 expression was rapidly and significantly increased by LL-37 treatment. LL-37 treatment also enhanced the production of EGR1. Moreover, small interfering RNA-mediated knockdown of EGR1 inhibited LL-37-enhanced ASC proliferation and migration. Activation of mitogen-activated protein kinases (MAPKs) was essential not only for LL-37-enhanced ASC proliferation and migration but also EGR1 expression; treatment with a specific inhibitor of extracellular signal-regulated kinase, p38, or c-Jun N-terminal kinase blocked the stimulatory effect of LL-37. EGR1 has a strong paracrine capability and can influence angiogenic factors in ASCs; therefore, we evaluated the secretion levels of vascular endothelial growth factor, thymosin beta-4, monocyte chemoattractant protein-1, and stromal cell-derived factor-1. LL-37 treatment increased the secretion of these regenerative factors. Moreover, treatment with the conditioned medium of ASCs pre-activated with LL-37 strongly promoted hair growth in vivo. CONCLUSIONS: These findings show that LL-37 increases EGR1 expression and MAPK activation, and that preconditioning of ASCs with LL-37 has a strong potential to promote hair growth in vivo. This study correlates LL-37 with MSC functions (specifically those of ASCs), including cell expansion, cell migration, and paracrine actions, which may be useful in terms of implantation for tissue regeneration. SN - 1757-6512 UR - https://www.unboundmedicine.com/medline/citation/27095351/LL_37_stimulates_the_functions_of_adipose_derived_stromal/stem_cells_via_early_growth_response_1_and_the_MAPK_pathway_ L2 - https://stemcellres.biomedcentral.com/articles/10.1186/s13287-016-0313-4 DB - PRIME DP - Unbound Medicine ER -