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• W3092678583 abstract "Although testosterone deficiency (TD) can be present among 1 in 5 men 40 years or older, the factors responsible for TD remain largely unknown. Leydig cells produce testosterone in the testes under the pulsatile control of luteinizing hormone (LH) from pituitary gland. Leydig stem cells have the potential to differentiate into adult Leydig cells that can lead to increasing testosterone however the factors underlying reasons for differentiation remain unknown. In the present study we evaluated the paracrine factors released from testicular microenvironment (TME), which is comprised of Sertoli and peritubular myoid cells, in modulating differentiation of Leydig stem cells to Adult Leydig cells and production of Testosterone. Additionally, we explored the underlying mechanism of action of these paracrine factors. A total of 13 men with testicular failure underwent testis biopsies for sperm retrieval were used for the study. Using an IRB approved protocol, about 10mg of testicular tissue from each of these men were processed for Leydig stem cell isolation, culture and characterized. Cytokine antibody array was performed to identify the paracrine factors released by Sertoli and Peritubular Myoid cells using unsorted and CD146+ve sorted cells. The cells were treated with hedgehog signaling agonist and antagonist to validate the specificity of paracrine factors identified. Immunostaining was performed to validate the changes at protein levels. Flow cytometry was performed to study the shift in the population of cells post Leptin treatment. GraphPad Prism was used for statistical analysis. All data were presented as the means ± SEM. The statistical significance between two groups was estimated by unpaired two-tailed t test. The current study revealed that the testicular microenvironment (TME), which is comprised of Sertoli and peritubular myoid cells, plays an instrumental role in Leydig stem cell differentiation and testosterone production under the regulation of the desert hedgehog signaling pathway (DHH). Additionally, identifying the paracrine factors that are released by TME and understanding their impact on Leydig stem cell (LSC) differentiation is key to unraveling and developing new niche-based therapy for TD. In the current study, LSCs were isolated from 13 men undergoing testis biopsies for sperm retrieval and evaluated the paracrine factors in the presence or absence of TME. TME-secreted leptin induces LSC differentiation and increases T production. These effects of Leptin on LSC differentiation and T production, however, are inversely concentration-dependent: positive at low doses and negative at higher doses. Mechanistically, Leptin acts on LSCs upstream of DHH; Leptin-DHH regulation functions unidirectionally insofar as DHH gain or loss of function has no effects on Leptin levels. Taken together these findings identify leptin as a key paracrine factor released by cells within the TME that modulates LSC differentiation and testosterone release from mature Leydig cells, a finding with important clinical implications for TD." @default.
• W3092678583 created "2020-10-22" @default.
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• W3092678583 date "2020-09-01" @default.
• W3092678583 modified "2023-10-16" @default.
• W3092678583 title "LEPTIN SECRETED FROM HUMAN LEYDIG STEM CELLS TARGETS HEDGEHOG SIGNALING TO AUGMENT ENDOGENOUS FUNCTION" @default.
• W3092678583 doi "https://doi.org/10.1016/j.fertnstert.2020.08.1147" @default.
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