Effects of Aging and Niche Microenvironment on Spermatogonial Stem Cell Self-Renewal

Ryu, Buom‐Yong; Orwig, Kyle E.; Oatley, Jon M.; Avarbock, Mary R.; Brinster, Ralph L.

doi:10.1634/stemcells.2005-0580

Cited by 240 publications

(207 citation statements)

References 30 publications

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“…The gradual loss of the differentiated touch dome lineage over weeks suggests that neural signals are important in the self-renewal of touch dome stem cells but are dispensable for differentiation of existing stem cells. That microenvironmental signals can prevent the exhaustion of somatic stem cells has been observed in other organs with respect to aging (28)(29)(30). Our results show a similar failure of stem cell maintenance when neural Shh is removed from the touch dome microenvironment.…”

Section: Discussionsupporting

confidence: 82%

Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium

Xiao

Thoresen

Williams

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The touch dome is a highly patterned mechanosensory structure in the epidermis composed of specialized keratinocytes in juxtaposition with innervated Merkel cells. The touch dome epithelium is maintained by tissue-specific stem cells, but the signals that regulate the touch dome are not known. We identify touch dome stem cells that are unique among epidermal cells in their activated Hedgehog signaling and ability to maintain the touch dome as a distinct lineage compartment. Skin denervation reveals that renewal of touch dome stem cells requires a perineural microenvironment, and deleting Sonic hedgehog (Shh) in neurons or Smoothened in the epidermis demonstrates that Shh is an essential niche factor that maintains touch dome stem cells. Up-regulation of Hedgehog signaling results in neoplastic expansion of touch dome keratinocytes but no Merkel cell neoplasia. These findings demonstrate that nerve-derived Shh is a critical regulator of lineage-specific stem cells that maintain specialized sensory compartments in the epidermis.

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Section: Discussionsupporting

confidence: 82%

Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium

Xiao

Thoresen

Williams

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Many of these signals and cross-talk between the somatic cells and stem cells are still unknown, although it is evident that some, like GDNF, have essential roles in embryonic development and are not restricted to the testis. In addition, recent work has demonstrated that the decline in spermatogenesis with aging reflects a degradation of the stem cell niche, rather than defects inherent to the stem cells (Ryu et al, 2006). Therefore, a thorough understanding of the niche and its experimental modulation may help devise new treatments for male infertility or possibly lead to the development of novel male contraceptives.…”

Section: Resultsmentioning

confidence: 99%

Gdnf signaling pathways within the mammalian spermatogonial stem cell niche

Hofmann

2008

Molecular and Cellular Endocrinology

204

178

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SummaryMammalian spermatogenesis is a complex process in which male germ-line stem cells develop to ultimately form spermatozoa. Spermatogonial stem cells, or SSCs, are found in the basal compartment of the seminiferous epithelium. They self-renew to maintain the pool of stem cells throughout life, or they differentiate to generate a large number of germ cells. A balance between SSC self-renewal and differentiation in the adult testis is therefore essential to maintain normal spermatogenesis and fertility. Maintenance and self-renewal are tightly regulated by extrinsic signals from the surrounding microenvironment, called the spermatogonial stem cell niche. By physically supporting the SSCs and providing them with growth factors, the Sertoli cell is the main component of the niche. In addition, adhesion molecules that connect the SSCs to the basement membrane and cellular components of the interstitium between the seminiferous tubules are important regulators of the niche function. This review mainly focuses on glial cell line-derived neurotrophic factor (Gdnf), which is produced by Sertoli cells to maintain SSCs self-renewal, and the downstream signaling pathways induced by this crucial growth factor. Interactions between Gdnf and other signaling pathways that maintain self-renewal, as well as the role of novel SSC-and Sertoli cell-specific transcription factors, are also discussed.

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“…The physical wearing of the niche areas has been shown to affect stem cell properties, too: in mice, thinning of the subventricular zone, a neurogenic stem cell niche, has been associated with decrease of cell proliferation and neuroblast numbers (Luo et al 2006). Moreover, declining mouse testis weight with age has also been linked to reduction in levels of spermatogenesis (Ryu et al 2006). In the same manner, the physical reduction and wear of the limbal niche after the age of 60 could be correlated to the decelerated wound healing clinically observed in that age group, including the delayed corneal epithelial wound healing after injury or infections such as microbial keratitis or following surgery such as corneal keratoplasty (Constantinou et al 2009;Parmar et al 2006;Ibrahim et al 2009;van der Meulen et al 2008).…”

Section: Discussionmentioning

confidence: 99%

The impact of age on the physical and cellular properties of the human limbal stem cell niche

Notara¹,

Shortt

O’Callaghan³

et al. 2012

AGE

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The limbal niche in the corneoscleral junction of the eye, habitat of the limbal epithelial stem cells (LESC), facilitates corneal epithelial regeneration by providing physical support and chemical signalling. Anatomical structures within the limbus, namely, limbal epithelial crypts and focal stromal projections, are believed to function as a putative niche for LESCs. In this study, the impact of age on the topography of this niche was investigated. Also, the relationship between niche topography and limbal epithelial cell phenotype was assessed. Ex vivo imaging of the limbus in cadaveric tissue of donors aged from infancy to 90 years was carried out using electron and confocal microscopy. The data suggested that the area occupied by the crypts was sharply reduced after the age of 60 years. The niche microstructures also became smoother with donor age. The phenotypic assessment of cultured limbal epithelial cells harvested from donors of different ages showed that the levels of putative stem cell markers as well as telomerase activity and telomere length remained unchanged, regardless of niche topography. However, the colony forming efficiency of the cultures was significantly reduced with age (p<0.05). This is the first comprehensive study of the effect of age on the structural and phenotypic characteristics of the human limbal niche. The results have a significant biological value as they suggest a correlation of limbal architecture with decline of re-epithelialisation rate in older patients. Overall, the data also suggest that LESCs harvested from younger donors may be more suitable for cultured LESC therapy production.

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Effects of Aging and Niche Microenvironment on Spermatogonial Stem Cell Self-Renewal

Cited by 240 publications

References 30 publications

Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium

Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium

Gdnf signaling pathways within the mammalian spermatogonial stem cell niche

The impact of age on the physical and cellular properties of the human limbal stem cell niche

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