Expression of leptin receptor in mouse skin and the role of leptin receptor-positive cells in skin development and wound healing

doi:10.12307/2022.404

Abstract

Abstract: BACKGROUND: It is believed that leptin receptor (LepR) marks the adult bone marrow mesenchymal stem cells in mice and LepR+ cells contribute to the regeneration of fractured bone. However, the residence of LepR+ stromal cells in skin and the function of the population in skin development and repair are poorly understood.
OBJECTIVE: To investigate the expression of LepR in mouse skin and the role of LepR+ cells in development and tissue repair.
METHODS: The study was approved by the Experimental Animal Ethics and Use Committee of Shanghai Jiao Tong University with the approval No. 1504002. The LepR-Cre; tdTomato mice were generated by using the classic Cre-loxP system for tracing the expression of LepR in mouse skin. Flow cytometry was used to analyze surface markers on Tomato+ cells. A full-thickness skin excision wound model was constructed on the back of LepR-Cre; tdTomato mice to trace the distribution of LepR+ cells in skin wound healing. The LepR-Cre; Tsc1fl/fl mice for specific deletion of Tsc1 in LepR+ cells were constructed to identify the role of Tsc1 in mouse skin development.
RESULTS AND CONCLUSION: (1) LepR was expressed in dermal papilla, stroma, and dermal white adipose tissue in mice skin. (2) Immunofluorescence staining revealed that LepR+ cells partially co-expressed with stromal marker Vimentin and adipocyte marker Perilipin. Cell surface marker analysis showed that LepR lineage cells were negative for CD11b, CD45, and CD31, and positive for CD73 and Sca-1. LepR labeled a population of mesenchymal stem cells in mouse skin. (3) Punching experiment of LepR-Cre; tdTomato mice uncovered that LepR+ cells were involved in injury repair. (4) The LepR-Cre; Tsc1fl/fl mice presented the phenotype that the thickness of dermis and dermal white adipose tissue increased and the number of adipocytes increased significantly. It is concluded that LepR is expressed in mouse skin and cells of the LepR lineage in the skin are involved in tissue development and damage repair.

Key words: LepR lineage tracing, mesenchymal stem cells, skin, dermis, dermal white adipose tissue, development, wound healing, Tsc1

CLC Number:

Wang Ao, Chu Hongshang, Wu Hongguang, Li Ke, Liu Huijuan. Expression of leptin receptor in mouse skin and the role of leptin receptor-positive cells in skin development and wound healing[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(25): 3993-3998.

Figures/Tables 5

References

[1] PAN WW, MYERS MG JR. Leptin and the maintenance of elevated body weight. Nat Rev Neurosci. 2018;19(2):95-105.
[2] TRINH T, BROXMEYER HE. Role for Leptin and Leptin Receptors in Stem Cells During Health and Diseases. Stem Cell Rev Rep. 2021;17(2):511-522.
[3] FRIEDMAN JM. Leptin and the endocrine control of energy balance. Nat Metab. 2019;1(8):754-764.
[4] FU X, LIU G, HALIM A, et al. Mesenchymal Stem Cell Migration and Tissue Repair. Cells. 2019;8(8):784.
[5] KFOURY Y, SCADDEN DT. Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell. 2015;16(3):239-253.
[6] TARTAGLIA LA. The leptin receptor. J Biol Chem. 1997;272(10):6093-6096.
[7] TRINH T, ROPA J, ALJOUFI A, et al. Leptin receptor, a surface marker for a subset of highly engrafting long-term functional hematopoietic stem cells. Leukemia. 2020 Nov 7. doi: 10.1038/s41375-020-01079-z.
[8] ZHOU BO, YUE R, MURPHY MM, et al. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell. 2014;15(2):154-168.
[9] DING L, SAUNDERS TL, ENIKOLOPOV G, et al. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481(7382):457-462.
[10] COMAZZETTO S, MURPHY MM, BERTO S, et al. Restricted Hematopoietic Progenitors and Erythropoiesis Require SCF from Leptin Receptor+ Niche Cells in the Bone Marrow. Cell Stem Cell. 2019;24(3):477-486.
[11] DECKER M, MARTINEZ-MORENTIN L, WANG G, et al. Leptin-receptor-expressing bone marrow stromal cells are myofibroblasts in primary myelofibrosis. Nat Cell Biol. 2017;19(6):677-688.
[12] ZHANG D, ZHANG S, WANG J, et al. LepR-Expressing Stem Cells Are Essential for Alveolar Bone Regeneration. J Dent Res. 2020;99(11):1279-1286.
[13] ROGNONI E, WATT FM. Skin Cell Heterogeneity in Development, Wound Healing, and Cancer. Trends Cell Biol. 2018;28(9):709-722.
[14] FUCHS E. Skin Stem Cells in Silence, Action, and Cancer. Stem Cell Reports. 2018;10(5):1432-1438.
[15] HORSLEY V. Skin in the Game: Stem Cells in Repair, Cancer, and Homeostasis. Cell. 2020;181(3):492-494.
[16] DEKONINCK S, BLANPAIN C. Stem cell dynamics, migration and plasticity during wound healing. Nat Cell Biol. 2019;21(1):18-24.
[17] GUERRERO-JUAREZ CF, PLIKUS MV. Emerging nonmetabolic functions of skin fat. Nat Rev Endocrinol. 2018;14(3):163-173.
[18] HU MS, BORRELLI MR, LORENZ HP, et al. Mesenchymal Stromal Cells and Cutaneous Wound Healing: A Comprehensive Review of the Background, Role, and Therapeutic Potential. Stem Cells Int. 2018;2018:6901983.
[19] RODRIGUES M, KOSARIC N, BONHAM CA, et al. Wound Healing: A Cellular Perspective. Physiol Rev. 2019;99(1):665-706.
[20] BOOTHBY IC, COHEN JN, ROSENBLUM MD. Regulatory T cells in skin injury: At the crossroads of tolerance and tissue repair. Sci Immunol. 2020;5(47): eaaz9631.
[21] SAXTON RA, SABATINI DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168(6):960-976.
[22] LAPLANTE M, SABATINI DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-293.
[23] KIM J, GUAN KL. mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol. 2019;21(1):63-71.
[24] CRINO PB, NATHANSON KL, HENSKE EP. The tuberous sclerosis complex. N Engl J Med. 2006;355(13):1345-1356.
[25] KRETZSCHMAR K, WATT FM. Lineage tracing. Cell. 2012;148(1-2):33-45.
[26] HORIE T, PARK G, INABA Y, et al. MAPK Erk5 in Leptin Receptor‒Expressing Neurons Controls Body Weight and Systemic Energy Homeostasis in Female Mice. Endocrinology. 2019;160(12):2837-2848.
[27] DING X, BLOCH W, IDEN S, et al.mTORC1 and mTORC2 regulate skin morphogenesis and epidermal barrier formation. Nat Commun. 2016;7:13226.
[28] CIBRIAN D, DE LA FUENTE H, SÁNCHEZ-MADRID F. Metabolic Pathways That Control Skin Homeostasis and Inflammation. Trends Mol Med. 2020;26(11): 975-986.
[29] KRAMANN R, SCHNEIDER RK, DIROCCO DP, et al. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell. 2015;16(1): 51-66.
[30] CURRIE JD, GROSSER L, MURAWALA P, et al. The Prrx1 limb enhancer marks an adult subpopulation of injury-responsive dermal fibroblasts. Biol Open. 2019; 8(7):bio043711.
[31] LEAVITT T, HU MS, BORRELLI MR, et al. Prrx1 Fibroblasts Represent a Pro-fibrotic Lineage in the Mouse Ventral Dermis. Cell Rep. 2020;33(6):108356.
[32] ABBASI S, SINHA S, LABIT E, et al. Distinct Regulatory Programs Control the Latent Regenerative Potential of Dermal Fibroblasts during Wound Healing. Cell Stem Cell. 2020;27(3):396-412.e6.
[33] TIKHONOVA AN, DOLGALEV I, HU H, et al. The bone marrow microenvironment at single-cell resolution. Nature. 2019;569(7755):222-228.
[34] BLANPAIN C, SIMONS BD. Unravelling stem cell dynamics by lineage tracing. Nat Rev Mol Cell Biol. 2013;14(8):489-502.
[35] EL AGHA E, KRAMANN R, SCHNEIDER RK, et al. Mesenchymal Stem Cells in Fibrotic Disease. Cell Stem Cell. 2017;21(2):166-177.
[36] SEROWOKY MA, ARATA CE, CRUMP JG, et al. Skeletal stem cells: insights into maintaining and regenerating the skeleton. Development. 2020;147(5): dev179325.
[37] RIFFAULT M, JOHNSON GP, OWEN MM, et al. Loss of Adenylyl Cyclase 6 in Leptin Receptor-Expressing Stromal Cells Attenuates Loading-Induced Endosteal Bone Formation. JBMR Plus. 2020;4(11):e10408.
[38] FUCHS E, BLAU HM. Tissue Stem Cells: Architects of Their Niches. Cell Stem Cell. 2020;27(4):532-556.
[39] MACHADO L, GEARA P, CAMPS J, et al. Tissue damage induces a conserved stress response that initiates quiescent muscle stem cell activation. Cell Stem Cell. 2021;28(6):1125-1135.e7.
[40] WELLS JM, WATT FM. Diverse mechanisms for endogenous regeneration and repair in mammalian organs. Nature. 2018;557(7705):322-328.
[41] LIU GY, SABATINI DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 2020;21(4):183-203.
[42] HENSKE EP, JÓŹWIAK S, KINGSWOOD JC, et al. Tuberous sclerosis complex. Nat Rev Dis Primers. 2016;2:16035.
[43] MENG D, FRANK AR, JEWELL JL. mTOR signaling in stem and progenitor cells. Development. 2018;145(1):dev152595.
[44] XIANG X, ZHAO J, XU G, et al. mTOR and the differentiation of mesenchymal stem cells. Acta Biochim Biophys Sin (Shanghai). 2011;43(7):501-510.
[45] HE D, WU H, XIANG J, et al. Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway. Nat Commun. 2020;11(1):37.
[46] ROBB KP, FITZGERALD JC, BARRY F, et al. Mesenchymal stromal cell therapy: progress in manufacturing and assessments of potency. Cytotherapy. 2019; 21(3):289-306.
[47] GOLCHIN A, FARAHANY TZ, KHOJASTEH A, et al. The Clinical Trials of Mesenchymal Stem Cell Therapy in Skin Diseases: An Update and Concise Review. Curr Stem Cell Res Ther. 2019;14(1):22-33.
[48] ZHANG R, MA J, HAN J, et al. Mesenchymal stem cell related therapies for cartilage lesions and osteoarthritis. Am J Transl Res. 2019;11(10):6275-6289.
[49] STAFF NP, JONES DT, SINGER W. Mesenchymal Stromal Cell Therapies for Neurodegenerative Diseases. Mayo Clin Proc. 2019;94(5):892-905.
[50] CAPLAN AI, CORREA D. The MSC: an injury drugstore. Cell Stem Cell. 2011;9(1): 11-15.