Aging is associated with an expansion of CD49fhi mammary stem cells that show a decline in function and increased transformation potential

Dong, Qiaoxiang; Gao, Hui; Shi, Yuanshuo; Zhang, Fuchuang; Gu, Xiang; Wu, Anqi; Wang, Danhan; Chen, Yuanhong; Bandyopadhyay, Abhik; Yeh, I-Tien; Daniel, Benjamin S.; Chen, Yi; Zou, Yi; Rebel, Vivienne L; Walter, Christi A.; Lu, Jianxin; Huang, Changjiang; Sun, Lu-Zhe

doi:10.18632/aging.101082

Cited by 11 publications

(86 citation statements)

References 67 publications

(86 reference statements)

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“…Future studies may focus on the inflammatory cytokines and immune cell types enriched in aged mammary glands as detected herein to further delineate their exact contribution to tumor formation and progression. Of note, basal-like luminal cells have been reported in aged mice with mammary hyperplasia and in older women ( Dong et al, 2016 ; Garbe et al, 2012 ; Pelissier Vatter et al, 2018 ), but are undetectable in our healthy aged mice, suggesting that these cells might represent a more-aberrant population that is usually absent in normal murine mammary glands.…”

Section: Discussionmentioning

confidence: 64%

“…Although recent single-cell RNA sequencing (scRNA-seq) studies have characterized changes during embryonic development, puberty, and pregnancy ( Bach et al, 2017 ; Giraddi et al, 2018 ; Pal et al, 2017 ; Wuidart et al, 2018 ), little is known about the alterations associated with aging, an important aspect of mammary development closely related to breast cancer ( Jenkins et al, 2014 ). Although mammography, histology, and molecular analyses have revealed prominent changes with age, including decreased mammographic density, altered epithelial proportions, and reduced connective tissue ( Azam et al, 2019 ; Dong et al, 2016 ; Garbe et al, 2012 ; Gertig et al, 1999 ; Hart et al, 1989 ; Hutson et al, 1985 ; McCormack et al, 2010 ; Pelissier Vatter et al, 2018 ; Pelissier et al, 2014 ), systematic single-cell transcriptome profiling can better capture age-associated effects at a higher resolution and on a larger scale. Moreover, given that increased age is strongly associated with breast cancer susceptibility in human and mouse models ( Jenkins et al, 2014 ; LaBarge et al, 2016 ; Raafat et al, 2012 ), a single-cell atlas for aged mammary glands could help fill the gaps in our knowledge of aging and cancer risk.…”

Section: Introductionmentioning

confidence: 99%

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Aging-Associated Alterations in Mammary Epithelia and Stroma Revealed by Single-Cell RNA Sequencing

Shapiro

Tsiobikas

et al. 2020

Cell Reports

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SUMMARY Aging is closely associated with increased susceptibility to breast cancer, yet there have been limited systematic studies of aging-induced alterations in the mammary gland. Here, we leverage high-throughput single-cell RNA sequencing to generate a detailed transcriptomic atlas of young and aged murine mammary tissues. By analyzing epithelial, stromal, and immune cells, we identify age-dependent alterations in cell proportions and gene expression, providing evidence that suggests alveolar maturation and physiological decline. The analysis also uncovers potential pro-tumorigenic mechanisms coupled to the age-associated loss of tumor suppressor function and change in microenvironment. In addition, we identify a rare, age-dependent luminal population co-expressing hormone-sensing and secretory-alveolar lineage markers, as well as two macrophage populations expressing distinct gene signatures, underscoring the complex heterogeneity of the mammary epithelia and stroma. Collectively, this rich single-cell atlas reveals the effects of aging on mammary physiology and can serve as a useful resource for understanding aging-associated cancer risk.

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Aging-Associated Alterations in Mammary Epithelia and Stroma Revealed by Single-Cell RNA Sequencing

Shapiro

Tsiobikas

et al. 2020

Cell Reports

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“…In the bone marrow, CD49a and CD49f have been reported to be discriminant for cells endowed with higher multipotency and stemness status [41]. However, it has been also shown that, in mammary stem cells, aging is associated with an increased expression of CD49f paralleled by a decline in function and increased transformation potential [42]. Regarding CD49a, it has been reported that selection using this integrin enhances the multipotentiality of mesenchymal stem cells [43].…”

Section: Discussionmentioning

confidence: 99%

Human Adipose-Derived Stem Cells in Madelung’s Disease: Morphological and Functional Characterization

Caponnetto

Manini²,

Bulfoni

et al. 2020

Cells

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Madelung Disease (MD) is a syndrome characterized by the accumulation of aberrant symmetric adipose tissue deposits. The etiology of this disease is yet to be elucidated, even though the presence of comorbidities, either genetic or environmental, has been reported. For this reason, establishing an in vitro model for MD is considered crucial to get insights into its physiopathology. We previously established a protocol for isolation and culture of stem cells from diseased tissues. Therefore, we isolated human adipose-derived stem cells (ASC) from MD patients and compared these cells with those isolated from healthy subjects in terms of surface phenotype, growth kinetic, adipogenic differentiation potential, and molecular alterations. Moreover, we evaluated the ability of the MD-ASC secretome to affect healthy ASC. The results reported a difference in the growth kinetic and surface markers of MD-ASC compared to healthy ASC but not in adipogenic differentiation. The most commonly described mitochondrial mutations were not observed. Still, MD-ASC secretome was able to shift the healthy ASC phenotype to an MD phenotype. This work provides evidence of the possibility of exploiting a patient-based in vitro model for better understanding MD pathophysiology, possibly favoring the development of novel target therapies.

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“…As a case in point, Garbe et al have shown the accumulation of multipotent progenitors during the aging of human mammary epithelia (7). Similarly, Dong et al have recently shown an age-associated increase in MaSC frequency in mouse mammary glands (6). Both reports described a decline in the function and an increased transformation potential of MaSC with aging.…”

Section: Fig 11mentioning

confidence: 97%

“…The well-known one is the procarcinogenic aging process, during which there is an accumulation of senescent cells, known to have proinflammatory and -tumorigenic paracrine effects mediated through the secretion of various cytokines and growth factors (3)(4)(5). Indeed, several lines of evidence indicated the presence of age-dependent accumulation of multipotent progenitor cells with a decline in function and alteration in the luminal-to-basal cell ratio (6,7). Moreover, senescence promoted cellular reprogramming in vivo through the secretion of high levels of interleukin-6 (IL-6) (8,9).…”

mentioning

confidence: 99%

Interleukin-8 Dedifferentiates Primary Human Luminal Cells to Multipotent Stem Cells

Al-Khalaf

Ghebeh²,

Wakil³

et al. 2020

Molecular and Cellular Biology

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During aging, cellular plasticity and senescence play important roles in tissue regeneration and the pathogenesis of different diseases, including cancer. We have recently shown that senescent breast luminal cells can activate their adjacent stromal fibroblasts. In the present report, we present clear evidence that these senescence-related active fibroblasts can dedifferentiate proliferating primary human luminal cells to multipotent stem cells in an interleukin-8 (IL-8)-dependent manner. This was confirmed using recombinant IL-8, while the truncated protein was not active. This IL-8-related dedifferentiation of luminal cells was mediated through the STAT3-dependent downregulation of p16INK4A and the microRNA miR-141. Importantly, these in vitro-generated mammary stem cells exhibited high molecular and cellular similarities to human mammary stem cells. They have also shown a long-term mammary gland-reconstituting ability and the capacity to produce milk postdelivery. Thereby, these IL-8-generated mammary stem cells could be of great value for autologous cell therapy procedures and also for biomedical research as well as drug development.

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Aging is associated with an expansion of CD49fhi mammary stem cells that show a decline in function and increased transformation potential

Cited by 11 publications

References 67 publications

Aging-Associated Alterations in Mammary Epithelia and Stroma Revealed by Single-Cell RNA Sequencing

Aging-Associated Alterations in Mammary Epithelia and Stroma Revealed by Single-Cell RNA Sequencing

Human Adipose-Derived Stem Cells in Madelung’s Disease: Morphological and Functional Characterization

Interleukin-8 Dedifferentiates Primary Human Luminal Cells to Multipotent Stem Cells

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