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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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Nestin-expressing cells protrude from blood vessel walls and transform into Leydig cells. 14 d after EDS, nestin-immunoreactive cells begin to protrude (arrows) from intertubular vessel walls (a and b) and begin to form cell clusters in their direct vicinity (c and d). The orientation of such a vessel between newly formed cell clusters (d, indicated by an arrow) and sites where transdifferentiating progenitor cells are still in contact with the vessel they derive from (c, red arrows) are shown. These clusters consist of cells that either coexpress nestin (brown) and CytP450 (blue), or express Cyt P450 only (e and f). 1 wk later, nestin+ cells are visible at a peritubular position (g and h), and newly formed Leydig cells are only occasionally (h, day 20) or not at all (i, day 21) nestin positive. At this time (k, day 21), the number of proliferating (BrdU labeled) vascular wall cells (arrows) is much lower than at d 2 after EDS (j). T, seminiferous tubules.
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fig3: Nestin-expressing cells protrude from blood vessel walls and transform into Leydig cells. 14 d after EDS, nestin-immunoreactive cells begin to protrude (arrows) from intertubular vessel walls (a and b) and begin to form cell clusters in their direct vicinity (c and d). The orientation of such a vessel between newly formed cell clusters (d, indicated by an arrow) and sites where transdifferentiating progenitor cells are still in contact with the vessel they derive from (c, red arrows) are shown. These clusters consist of cells that either coexpress nestin (brown) and CytP450 (blue), or express Cyt P450 only (e and f). 1 wk later, nestin+ cells are visible at a peritubular position (g and h), and newly formed Leydig cells are only occasionally (h, day 20) or not at all (i, day 21) nestin positive. At this time (k, day 21), the number of proliferating (BrdU labeled) vascular wall cells (arrows) is much lower than at d 2 after EDS (j). T, seminiferous tubules.

Mentions: 14 d after EDS, nestin-positive cells begin to protrude from the vessel walls (Fig. 3, a–c) and to accumulate in their vicinity in form of clusters (Fig. 3 d), strikingly similar to the (CytP450 immunoreactive) Leydig cell clusters observed at that time (Fig. 1 a). Conditions where these cell clusters are still in contact with the blood vessel walls they derive from are detectable (Fig. 3 c). As revealed by double staining, the clusters consist of cells expressing either both nestin and CytP450, or only CytP450 (Fig. 3, e and f), indicating a process in which nestin-immunoreactive cells, during and/or after their displacement from vessel walls, first acquire steroidogenic properties (expression of CytP450) and then loose nestin, finally resulting in typical Leydig cells. This conversion into Leydig cells is accompanied also by a loss of SMA immunoreactivity (not depicted), providing further evidence for a transdifferentiation phenomenon. Approximately 1 wk later, when newly formed Leydig cells are abundant and localized primarily around the tubular compartments, nestin expression is generally reduced but still clearly detectable at larger blood vessels (Fig. 3 g). Newly formed Leydig cells that still display nestin immunoreactivity are only rarely to be found at d 20 (Fig. 3 h) and are nearly undetectable at d 21 (Fig. 3 i), indicating a faster transformation process at that time. In contrast to the situation early after EDS treatment, the rapid and abundant transformation is not accompanied by a pronounced cell division activity. Note that the number of BrdU-labeled nuclei of stem cell–like progenitors is several fold higher at d 2 (Fig. 3 j) than at d 21 after EDS (Fig. 3 k). Thus, proliferation of the Leydig cell progenitors predominates during the first week after EDS, whereas their transformation begins at d 14 and accelerates 1 wk later.


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)

Nestin-expressing cells protrude from blood vessel walls and transform into Leydig cells. 14 d after EDS, nestin-immunoreactive cells begin to protrude (arrows) from intertubular vessel walls (a and b) and begin to form cell clusters in their direct vicinity (c and d). The orientation of such a vessel between newly formed cell clusters (d, indicated by an arrow) and sites where transdifferentiating progenitor cells are still in contact with the vessel they derive from (c, red arrows) are shown. These clusters consist of cells that either coexpress nestin (brown) and CytP450 (blue), or express Cyt P450 only (e and f). 1 wk later, nestin+ cells are visible at a peritubular position (g and h), and newly formed Leydig cells are only occasionally (h, day 20) or not at all (i, day 21) nestin positive. At this time (k, day 21), the number of proliferating (BrdU labeled) vascular wall cells (arrows) is much lower than at d 2 after EDS (j). T, seminiferous tubules.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172461&req=5

fig3: Nestin-expressing cells protrude from blood vessel walls and transform into Leydig cells. 14 d after EDS, nestin-immunoreactive cells begin to protrude (arrows) from intertubular vessel walls (a and b) and begin to form cell clusters in their direct vicinity (c and d). The orientation of such a vessel between newly formed cell clusters (d, indicated by an arrow) and sites where transdifferentiating progenitor cells are still in contact with the vessel they derive from (c, red arrows) are shown. These clusters consist of cells that either coexpress nestin (brown) and CytP450 (blue), or express Cyt P450 only (e and f). 1 wk later, nestin+ cells are visible at a peritubular position (g and h), and newly formed Leydig cells are only occasionally (h, day 20) or not at all (i, day 21) nestin positive. At this time (k, day 21), the number of proliferating (BrdU labeled) vascular wall cells (arrows) is much lower than at d 2 after EDS (j). T, seminiferous tubules.
Mentions: 14 d after EDS, nestin-positive cells begin to protrude from the vessel walls (Fig. 3, a–c) and to accumulate in their vicinity in form of clusters (Fig. 3 d), strikingly similar to the (CytP450 immunoreactive) Leydig cell clusters observed at that time (Fig. 1 a). Conditions where these cell clusters are still in contact with the blood vessel walls they derive from are detectable (Fig. 3 c). As revealed by double staining, the clusters consist of cells expressing either both nestin and CytP450, or only CytP450 (Fig. 3, e and f), indicating a process in which nestin-immunoreactive cells, during and/or after their displacement from vessel walls, first acquire steroidogenic properties (expression of CytP450) and then loose nestin, finally resulting in typical Leydig cells. This conversion into Leydig cells is accompanied also by a loss of SMA immunoreactivity (not depicted), providing further evidence for a transdifferentiation phenomenon. Approximately 1 wk later, when newly formed Leydig cells are abundant and localized primarily around the tubular compartments, nestin expression is generally reduced but still clearly detectable at larger blood vessels (Fig. 3 g). Newly formed Leydig cells that still display nestin immunoreactivity are only rarely to be found at d 20 (Fig. 3 h) and are nearly undetectable at d 21 (Fig. 3 i), indicating a faster transformation process at that time. In contrast to the situation early after EDS treatment, the rapid and abundant transformation is not accompanied by a pronounced cell division activity. Note that the number of BrdU-labeled nuclei of stem cell–like progenitors is several fold higher at d 2 (Fig. 3 j) than at d 21 after EDS (Fig. 3 k). Thus, proliferation of the Leydig cell progenitors predominates during the first week after EDS, whereas their transformation begins at d 14 and accelerates 1 wk later.

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