TY - JOUR
T1 - Subcutaneous Leydig Stem Cell Autograft
T2 - A Promising Strategy to Increase Serum Testosterone
AU - Arora, Himanshu
AU - Zuttion, Marilia Sanches Santos Rizzo
AU - Nahar, Bruno
AU - Lamb, Dolores
AU - Hare, Joshua M.
AU - Ramasamy, Ranjith
N1 - Funding Information:
The authors thank Alexander Agoulnik, Florida International University, for mentorship and guidance. This work was supported by the American Urological Association Research Scholar Award and Stanley Glaser Award (to R.R.) as well as NIH grants 1R01 HL137355, 1R01 HL107110, 1R01 HL134558, 5R01 CA136387, and 5UM1 HL113460 and Soffer Family Foundation (to J.M.H.).
Publisher Copyright:
© 2018 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press
PY - 2019/1
Y1 - 2019/1
N2 - Exogenous testosterone therapy can be used to treat testosterone deficiency; however, it has several adverse effects including infertility due to negative feedback on the hypothalamic–pituitary–gonadal (HPG) axis. Leydig stem cell (LSC) transplantation could provide a new strategy for treating testosterone deficiency, but clinical translatability of injecting stem cells inside the testis is not feasible. Here, we explore the feasibility of subcutaneously autografting LSCs in combination with Sertoli and myoid cells to increase testosterone. We also studied whether the grafted LSCs can be regulated by the HPG axis and the molecular mechanism behind this regulation. LSCs were isolated from the testes of 12-week-old C57BL/6 mice, and subcutaneously autografted in combination with Sertoli cells and myoid cells. We found that LSCs alone were incapable of self-renewal and differentiation. However, in combination with Sertoli cells and myoid cells, LSCs underwent self-renewal as well as differentiation into mature Leydig cells. As a result, the recipient mice that received the LSC autograft showed testosterone production with preserved luteinizing hormone. We found that testosterone production from the autograft was regulated by hedgehog (HH) signaling. Gain of function and loss of function study confirmed that Desert HH (DHH) agonist increased and DHH antagonist decreased testosterone production from autograft. This study is the first to demonstrate that LSCs, when autografted subcutaneously in combination with Sertoli cells and myoid cells, can increase testosterone production. Therefore, LSC autograft may provide a new treatment for testosterone deficiency while simultaneously preserving the HPG axis. Stem Cells Translational Medicine 2019;8:58–65.
AB - Exogenous testosterone therapy can be used to treat testosterone deficiency; however, it has several adverse effects including infertility due to negative feedback on the hypothalamic–pituitary–gonadal (HPG) axis. Leydig stem cell (LSC) transplantation could provide a new strategy for treating testosterone deficiency, but clinical translatability of injecting stem cells inside the testis is not feasible. Here, we explore the feasibility of subcutaneously autografting LSCs in combination with Sertoli and myoid cells to increase testosterone. We also studied whether the grafted LSCs can be regulated by the HPG axis and the molecular mechanism behind this regulation. LSCs were isolated from the testes of 12-week-old C57BL/6 mice, and subcutaneously autografted in combination with Sertoli cells and myoid cells. We found that LSCs alone were incapable of self-renewal and differentiation. However, in combination with Sertoli cells and myoid cells, LSCs underwent self-renewal as well as differentiation into mature Leydig cells. As a result, the recipient mice that received the LSC autograft showed testosterone production with preserved luteinizing hormone. We found that testosterone production from the autograft was regulated by hedgehog (HH) signaling. Gain of function and loss of function study confirmed that Desert HH (DHH) agonist increased and DHH antagonist decreased testosterone production from autograft. This study is the first to demonstrate that LSCs, when autografted subcutaneously in combination with Sertoli cells and myoid cells, can increase testosterone production. Therefore, LSC autograft may provide a new treatment for testosterone deficiency while simultaneously preserving the HPG axis. Stem Cells Translational Medicine 2019;8:58–65.
KW - Fertility
KW - Hypogonadism
KW - Leydig cell
KW - Myoid cell
KW - Sertoli cell
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U2 - 10.1002/sctm.18-0069
DO - 10.1002/sctm.18-0069
M3 - Article
C2 - 30280521
AN - SCOPUS:85054294872
VL - 8
SP - 58
EP - 65
JO - Stem cells translational medicine
JF - Stem cells translational medicine
SN - 2157-6564
IS - 1
ER -