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Progenitor cells of the testosterone-producing Leydig cells revealed.

Davidoff MS, Middendorff R, Enikolopov G, Riethmacher D, Holstein AF, Müller D - J. Cell Biol. (2004)

Bottom Line: Their origin during ontogeny and regeneration processes is still a matter of debate.Here, we show that cells of testicular blood vessels, namely vascular smooth muscle cells and pericytes, are the progenitors of Leydig cells.Resembling stem cells of the nervous system, the Leydig cell progenitors are characterized by the expression of nestin.

View Article: PubMed Central - PubMed

Affiliation: Institute of Anatomy, University of Hamburg, Germany. davidoff@uke.uni-hamburg.de

ABSTRACT
The cells responsible for production of the male sex hormone testosterone, the Leydig cells of the testis, are post-mitotic cells with neuroendocrine characteristics. Their origin during ontogeny and regeneration processes is still a matter of debate. Here, we show that cells of testicular blood vessels, namely vascular smooth muscle cells and pericytes, are the progenitors of Leydig cells. Resembling stem cells of the nervous system, the Leydig cell progenitors are characterized by the expression of nestin. Using an in vivo model to induce and monitor the synchronized generation of a completely new Leydig cell population in adult rats, we demonstrate specific proliferation of vascular progenitors and their subsequent transdifferentiation into steroidogenic Leydig cells which, in addition, rapidly acquire neuronal and glial properties. These findings, shown to be representative also for ontogenetic Leydig cell formation and for the human testis, provide further evidence that cellular components of blood vessels can act as progenitor cells for organogenesis and repair.

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Schematic representation of transdifferentiation of vascular progenitors into Leydig cells. (a) Nestin-expressing (black) vascular smooth muscle cells (VSMC) and pericytes (PC) of testicular blood vessels, but not endothelial cells (EC) or peritubular myoid cells (MC), vigorously proliferate (indicated by red-labeled nuclei) during the first week after EDS-induced Leydig cell depletion. (b) Around d 14 after EDS, nestin-expressing VSMCs and PCs, now marked also by a transient expression of NF-H (green contour line), begin to protrude from intertubular vessels and begin to form cell clusters. By transdifferentiation, the cells first acquire steroidogenic properties (yellow, black dotted) and finally loose nestin, resulting in typical (yellow) Leydig cells (LC). (c and d) Time scale of Leydig cell (re)generation after EDS treatment (c) and during ontogenetic development (d). (c) Leydig cell depletion, marked by the absence of CytP450 (yellow), rapidly induces nestin expression (black) and proliferation activity (red). The conversion of proliferative into transformation activity (yellow, black dotted) is preceded by a transient expression of NF-H (green). (d) A similar correlation between CytP450, nestin, and NF-H expression is detectable during postnatal testis development.
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fig6: Schematic representation of transdifferentiation of vascular progenitors into Leydig cells. (a) Nestin-expressing (black) vascular smooth muscle cells (VSMC) and pericytes (PC) of testicular blood vessels, but not endothelial cells (EC) or peritubular myoid cells (MC), vigorously proliferate (indicated by red-labeled nuclei) during the first week after EDS-induced Leydig cell depletion. (b) Around d 14 after EDS, nestin-expressing VSMCs and PCs, now marked also by a transient expression of NF-H (green contour line), begin to protrude from intertubular vessels and begin to form cell clusters. By transdifferentiation, the cells first acquire steroidogenic properties (yellow, black dotted) and finally loose nestin, resulting in typical (yellow) Leydig cells (LC). (c and d) Time scale of Leydig cell (re)generation after EDS treatment (c) and during ontogenetic development (d). (c) Leydig cell depletion, marked by the absence of CytP450 (yellow), rapidly induces nestin expression (black) and proliferation activity (red). The conversion of proliferative into transformation activity (yellow, black dotted) is preceded by a transient expression of NF-H (green). (d) A similar correlation between CytP450, nestin, and NF-H expression is detectable during postnatal testis development.

Mentions: This paper identifies VSMCs and PCs as the progenitors of Leydig cells (summarized in Fig. 6). We show that the Leydig cell progenitor cells are characterized by (1) the expression of nestin, a marker protein for stem cells of the nervous system (Lendahl et al., 1990; Rietze et al., 2001; Sahlgren et al., 2001); (2) a transient up-regulation in these cells of NF-H, known to be expressed in the nervous system during the differentiation of stem cells into the neuronal lineage (Dahlstrand et al., 1995); and (3) that the newly formed Leydig cells rapidly become immunoreactive for diverse neuronal and glial markers. Thus, three independent lines of evidence point to a similarity between the vascular Leydig cell progenitors and stem cells/progenitors of the nervous system, consistent with and supporting findings (for review see Carmeliet, 2003) that neural and vascular systems use common genetic pathways. In this context, the recent identification of a factor (Arx), implicated in both brain development and Leydig cell differentiation (Kitamura et al., 2002), has to be noted.


Progenitor cells of the testosterone-producing Leydig cells revealed.

Davidoff MS, Middendorff R, Enikolopov G, Riethmacher D, Holstein AF, Müller D - J. Cell Biol. (2004)

Schematic representation of transdifferentiation of vascular progenitors into Leydig cells. (a) Nestin-expressing (black) vascular smooth muscle cells (VSMC) and pericytes (PC) of testicular blood vessels, but not endothelial cells (EC) or peritubular myoid cells (MC), vigorously proliferate (indicated by red-labeled nuclei) during the first week after EDS-induced Leydig cell depletion. (b) Around d 14 after EDS, nestin-expressing VSMCs and PCs, now marked also by a transient expression of NF-H (green contour line), begin to protrude from intertubular vessels and begin to form cell clusters. By transdifferentiation, the cells first acquire steroidogenic properties (yellow, black dotted) and finally loose nestin, resulting in typical (yellow) Leydig cells (LC). (c and d) Time scale of Leydig cell (re)generation after EDS treatment (c) and during ontogenetic development (d). (c) Leydig cell depletion, marked by the absence of CytP450 (yellow), rapidly induces nestin expression (black) and proliferation activity (red). The conversion of proliferative into transformation activity (yellow, black dotted) is preceded by a transient expression of NF-H (green). (d) A similar correlation between CytP450, nestin, and NF-H expression is detectable during postnatal testis development.
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Related In: Results  -  Collection

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fig6: Schematic representation of transdifferentiation of vascular progenitors into Leydig cells. (a) Nestin-expressing (black) vascular smooth muscle cells (VSMC) and pericytes (PC) of testicular blood vessels, but not endothelial cells (EC) or peritubular myoid cells (MC), vigorously proliferate (indicated by red-labeled nuclei) during the first week after EDS-induced Leydig cell depletion. (b) Around d 14 after EDS, nestin-expressing VSMCs and PCs, now marked also by a transient expression of NF-H (green contour line), begin to protrude from intertubular vessels and begin to form cell clusters. By transdifferentiation, the cells first acquire steroidogenic properties (yellow, black dotted) and finally loose nestin, resulting in typical (yellow) Leydig cells (LC). (c and d) Time scale of Leydig cell (re)generation after EDS treatment (c) and during ontogenetic development (d). (c) Leydig cell depletion, marked by the absence of CytP450 (yellow), rapidly induces nestin expression (black) and proliferation activity (red). The conversion of proliferative into transformation activity (yellow, black dotted) is preceded by a transient expression of NF-H (green). (d) A similar correlation between CytP450, nestin, and NF-H expression is detectable during postnatal testis development.
Mentions: This paper identifies VSMCs and PCs as the progenitors of Leydig cells (summarized in Fig. 6). We show that the Leydig cell progenitor cells are characterized by (1) the expression of nestin, a marker protein for stem cells of the nervous system (Lendahl et al., 1990; Rietze et al., 2001; Sahlgren et al., 2001); (2) a transient up-regulation in these cells of NF-H, known to be expressed in the nervous system during the differentiation of stem cells into the neuronal lineage (Dahlstrand et al., 1995); and (3) that the newly formed Leydig cells rapidly become immunoreactive for diverse neuronal and glial markers. Thus, three independent lines of evidence point to a similarity between the vascular Leydig cell progenitors and stem cells/progenitors of the nervous system, consistent with and supporting findings (for review see Carmeliet, 2003) that neural and vascular systems use common genetic pathways. In this context, the recent identification of a factor (Arx), implicated in both brain development and Leydig cell differentiation (Kitamura et al., 2002), has to be noted.

Bottom Line: Their origin during ontogeny and regeneration processes is still a matter of debate.Here, we show that cells of testicular blood vessels, namely vascular smooth muscle cells and pericytes, are the progenitors of Leydig cells.Resembling stem cells of the nervous system, the Leydig cell progenitors are characterized by the expression of nestin.

View Article: PubMed Central - PubMed

Affiliation: Institute of Anatomy, University of Hamburg, Germany. davidoff@uke.uni-hamburg.de

ABSTRACT
The cells responsible for production of the male sex hormone testosterone, the Leydig cells of the testis, are post-mitotic cells with neuroendocrine characteristics. Their origin during ontogeny and regeneration processes is still a matter of debate. Here, we show that cells of testicular blood vessels, namely vascular smooth muscle cells and pericytes, are the progenitors of Leydig cells. Resembling stem cells of the nervous system, the Leydig cell progenitors are characterized by the expression of nestin. Using an in vivo model to induce and monitor the synchronized generation of a completely new Leydig cell population in adult rats, we demonstrate specific proliferation of vascular progenitors and their subsequent transdifferentiation into steroidogenic Leydig cells which, in addition, rapidly acquire neuronal and glial properties. These findings, shown to be representative also for ontogenetic Leydig cell formation and for the human testis, provide further evidence that cellular components of blood vessels can act as progenitor cells for organogenesis and repair.

Show MeSH
Related in: MedlinePlus