Transplanted human p75-positive stem Leydig cells replace disrupted Leydig cells for testosterone production

Zhang, Min; Wang, Jiancheng; Deng, Chao; Jiang, Mei; Feng, Xin; Xia, Kai; Li, Weiqiang; Lai, Xiaomin; Xiao, Hang; Ge, Ren‐Shan; Gao, Yong; Xiang, Andy Peng

doi:10.1038/cddis.2017.531

Cited by 44 publications

(59 citation statements)

References 36 publications

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“…In contrast, negative control animals that received matrigel alone lacked any ALCs. The presence of differentiation in LCs in autografts was confirmed by immunofluorescence (IF) which stained ALCs positively for 3BHSD, STAR, and LHR (marker of LC) (Fig. D).…”

Section: Resultsmentioning

confidence: 82%

Subcutaneous Leydig Stem Cell Autograft: A Promising Strategy to Increase Serum Testosterone

Arora

Zuttion

Nahar

et al. 2018

Stem Cells Translational Medicine

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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

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Section: Resultsmentioning

confidence: 82%

Subcutaneous Leydig Stem Cell Autograft: A Promising Strategy to Increase Serum Testosterone

Arora

Zuttion

Nahar

et al. 2018

Stem Cells Translational Medicine

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“…As unlicensed substances they are applied as performance-enhancing substances and for doping. Ultimately, for ideal substitution hope rests on human stem Leydig cells transplanted to hypogonadal patients (84). The goal for these patients -at least those with an intact hypothalamo-pituitary system -would be that the testosterone production required would be provided by the transplanted Leydig cells and would be self-regulated by feedback to LH.…”

Section: Discussionmentioning

confidence: 99%

ENDOCRINE HISTORY: The history of discovery, synthesis and development of testosterone for clinical use

Nieschlag

2019

European Journal of Endocrinology

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As the most important male hormone, testosterone has an impact on almost all organs and body functions. The biological effects of testosterone and the testes have been known since antiquity, long before testosterone was identified as the active agent. Practical applications of this knowledge were castration of males to produce obedient servants, for punishment, for preservation of the prepubertal soprano voice and even for treatment of diseases. Testes were used in organotherapy and transplanted as treatment for symptoms of hypogonadism on a large scale, although these practices had only placebo effects. In reaction to such malpractice in the first half of the 20th century science and the young pharmaceutical industry initiated the search for the male hormone. After several detours together with their teams in 1935, Ernst Laqueur (Amsterdam) isolated and Adolf Butenandt (Gdansk) as well as Leopold Ruzicka (Zürich) synthesized testosterone. Since then testosterone has been available for clinical use. However, when given orally, testosterone is inactivated in the liver, so that parenteral forms of administration or modifications of the molecule had to be found. Over 85 years the testosterone preparations have been slowly improved so that now physiological serum levels can be achieved.

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“…Our previous study demonstrated that SLCs are multipotent stem cells and can differentiate into adipocytes. 24 We performed a Figure 8A). We used qPCR to confirm the mRNA levels of these genes (Dlk1, Fabp4 and Lpl) and Western blotting to measure the protein levels of their products.…”

Section: Fhf1 Prevents the Transition Of Stem Cells Into Adipocyte mentioning

confidence: 99%

Fibroblast growth factor homologous factor 1 stimulates Leydig cell regeneration from stem cells in male rats

Chen

et al. 2019

J Cellular Molecular Medi

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Fibroblast growth factor homologous factor 1 (FHF1) is an intracellular protein that does not bind to cell surface fibroblast growth factor receptor. Here, we report that FHF1 is abundantly present in Leydig cells with up‐regulation during its development. Adult male Sprague Dawley rats were intraperitoneally injected with 75 mg/kg ethane dimethane sulphonate (EDS) to ablate Leydig cells to initiate their regeneration. Then, rats daily received intratesticular injection of FHF1 (0, 10 and 100 ng/testis) from post‐EDS day 14 for 14 days. FHF1 increased serum testosterone levels without affecting the levels of luteinizing hormone and follicle‐stimulating hormone. FHF1 increased the cell number staining with HSD11B1, a biomarker for Leydig cells at the advanced stage, without affecting the cell number staining with CYP11A1, a biomarker for all Leydig cells. FHF1 did not affect PCNA‐labelling index in Leydig cells. FHF1 increased Leydig cell mRNA ( Lhcgr , Scarb1 , Star , Cyp11a1 , Hsd3b1 , Cyp17a1 , Hsd17b3, Insl3 , Nr5a1 and Hsd11b1 ) and their protein levels in vivo. FHF1 increased preadipocyte biomarker Dlk1 mRNA level and decreased fully differentiated adipocyte biomarker ( Fabp4 and Lpl ) mRNA and their protein levels. In conclusion, FHF1 promotes Leydig cell regeneration from stem cells while inhibiting the differentiation of preadipocyte/stem cells into adipocytes in EDS‐treated testis.

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Transplanted human p75-positive stem Leydig cells replace disrupted Leydig cells for testosterone production

Cited by 44 publications

References 36 publications

Subcutaneous Leydig Stem Cell Autograft: A Promising Strategy to Increase Serum Testosterone

Subcutaneous Leydig Stem Cell Autograft: A Promising Strategy to Increase Serum Testosterone

ENDOCRINE HISTORY: The history of discovery, synthesis and development of testosterone for clinical use

Fibroblast growth factor homologous factor 1 stimulates Leydig cell regeneration from stem cells in male rats

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