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Mechanisms Linking Quiescence, Proliferation and Differentiation of Adult Stem Cells to Organismal Aging and Aging-Associated Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 22663

Special Issue Editor

Dr. Vladimir Titorenko

E-Mail Website1 Website2
Guest Editor
Biology Department, Concordia University, Montreal, QC, Canada
Interests: aging; cancer; cell cycle; lipid metabolism; mitochondria; proteomics; lipidomics; metabolomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Quiescent adult stem cells in mammals and humans are resistant to stresses and display an enhanced ability to survive. These cells can self-renew by dividing asymmetrically to maintain a population of quiescent cells and to produce daughter progenitor cells that can then mature into one or more types of fully differentiated cells. All of these traits of quiescent adult stem cells underlie tissue repair and regeneration and are indispensable to the growth, development, and health of the adult body. An aging-associated decline in the number of adult stem cells and in their abilities to sustain quiescence, proliferate, and differentiate has been implicated in the pathophysiology of cancer and many other diseases of old age. Specific genetic, dietary, and pharmacological interventions can delay the onset of aging-associated diseases because they slow down the age-related numerical and functional decline of quiescent adult stem cells. The focus of this International Journal of Molecular Sciences Special Issue is on mechanisms that link quiescence, proliferation, and differentiation of adult stem cells to organismal aging and aging-associated diseases. The Special Issue will highlight recent progress and outline the critical unanswered questions and directions for future research in this vibrant and rapidly evolving field.

Dr. Vladimir Titorenko
Guest Editor

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Published Papers (6 papers)

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Research

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17 pages, 2622 KiB  
Article
In Vivo Pre-Instructed HSCs Robustly Execute Asymmetric Cell Divisions In Vitro
by Mukul Girotra, Vincent Trachsel, Aline Roch and Matthias P. Lutolf
Int. J. Mol. Sci. 2020, 21(21), 8225; https://doi.org/10.3390/ijms21218225 - 3 Nov 2020
Cited by 7 | Viewed by 2497
Abstract
Hematopoietic stem cells (HSCs) are responsible for life-long production of all mature blood cells. Under homeostasis, HSCs in their native bone marrow niches are believed to undergo asymmetric cell divisions (ACDs), with one daughter cell maintaining HSC identity and the other committing to [...] Read more.
Hematopoietic stem cells (HSCs) are responsible for life-long production of all mature blood cells. Under homeostasis, HSCs in their native bone marrow niches are believed to undergo asymmetric cell divisions (ACDs), with one daughter cell maintaining HSC identity and the other committing to differentiate into various mature blood cell types. Due to the lack of key niche signals, in vitro HSCs differentiate rapidly, making it challenging to capture and study ACD. To overcome this bottleneck, in this study, we used interferon alpha (IFNα) treatment to ”pre-instruct” HSC fate directly in their native niche, and then systematically studied the fate of dividing HSCs in vitro at the single cell level via time-lapse analysis, as well as multigene and protein expression analysis. Triggering HSCs’ exit from dormancy via IFNα was found to significantly increase the frequency of asynchronous divisions in paired daughter cells (PDCs). Using single-cell gene expression analyses, we identified 12 asymmetrically expressed genes in PDCs. Subsequent immunocytochemistry analysis showed that at least three of the candidates, i.e., Glut1, JAM3 and HK2, were asymmetrically distributed in PDCs. Functional validation of these observations by colony formation assays highlighted the implication of asymmetric distribution of these markers as hallmarks of HSCs, for example, to reliably discriminate committed and self-renewing daughter cells in dividing HSCs. Our data provided evidence for the importance of in vivo instructions in guiding HSC fate, especially ACD, and shed light on putative molecular players involved in this process. Understanding the mechanisms of cell fate decision making should enable the development of improved HSC expansion protocols for therapeutic applications. Full article
(This article belongs to the Special Issue Mechanisms Linking Quiescence, Proliferation and Differentiation of Adult Stem Cells to Organismal Aging and Aging-Associated Diseases)
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15 pages, 3312 KiB  
Article
Obesity-Altered Adipose Stem Cells Promote Radiation Resistance of Estrogen Receptor Positive Breast Cancer through Paracrine Signaling
by Rachel A. Sabol, Vidal A. Villela, Alexandra Denys, Benjamin T. Freeman, Alifiani B. Hartono, Rachel M. Wise, Mark A. A. Harrison, Maxwell B. Sandler, Fokhrul Hossain, Lucio Miele and Bruce A. Bunnell
Int. J. Mol. Sci. 2020, 21(8), 2722; https://doi.org/10.3390/ijms21082722 - 15 Apr 2020
Cited by 23 | Viewed by 3609
Abstract
Obesity is associated with poorer responses to chemo- and radiation therapy for breast cancer, which leads to higher mortality rates for obese women who develop breast cancer. Adipose stem cells (ASCs) are an integral stromal component of the tumor microenvironment (TME). In this [...] Read more.
Obesity is associated with poorer responses to chemo- and radiation therapy for breast cancer, which leads to higher mortality rates for obese women who develop breast cancer. Adipose stem cells (ASCs) are an integral stromal component of the tumor microenvironment (TME). In this study, the effects of obesity-altered ASCs (obASCs) on estrogen receptor positive breast cancer cell’s (ER+BCCs) response to radiotherapy (RT) were evaluated. We determined that BCCs had a decreased apoptotic index and increased surviving fraction following RT when co-cultured with obASCs compared to lnASCs or non-co-cultured cells. Further, obASCs reduced oxidative stress and induced IL-6 expression in co-cultured BCCs after radiation. obASCs produce increased levels of leptin relative to ASCs from normal-weight individuals (lnASCs). obASCs upregulate the expression of IL-6 compared to non-co-cultured BCCs, but BCCs co-cultured with leptin knockdown obASCs did not upregulate IL-6. The impact of shLeptin obASCs on radiation resistance of ER+BCCs demonstrate a decreased radioprotective ability compared to shControl obASCs. Key NOTCH signaling players were enhanced in ER+BBCs following co-culture with shCtrl obASCs but not shLep obASCs. This work demonstrates that obesity-altered ASCs, via enhanced secretion of leptin, promote IL-6 and NOTCH signaling pathways in ER+BCCs leading to radiation resistance. Full article
(This article belongs to the Special Issue Mechanisms Linking Quiescence, Proliferation and Differentiation of Adult Stem Cells to Organismal Aging and Aging-Associated Diseases)
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19 pages, 2986 KiB  
Article
Pharmacological Stimulation of Nurr1 Promotes Cell Cycle Progression in Adult Hippocampal Neural Stem Cells
by Haena Moon, Seong Gak Jeon, Jin-il Kim, Hyeon soo Kim, Sangho Lee, Dongok Kim, Seungjoon Park, Minho Moon and Hyunju Chung
Int. J. Mol. Sci. 2020, 21(1), 4; https://doi.org/10.3390/ijms21010004 - 18 Dec 2019
Cited by 8 | Viewed by 3844
Abstract
Nuclear receptor related-1 (Nurr1) protein performs a crucial role in hippocampal neural stem cell (hNSC) development as well as cognitive functions. We previously demonstrated that the pharmacological stimulation of Nurr1 by amodiaquine (AQ) promotes spatial memory by enhancing adult hippocampal neurogenesis. However, the [...] Read more.
Nuclear receptor related-1 (Nurr1) protein performs a crucial role in hippocampal neural stem cell (hNSC) development as well as cognitive functions. We previously demonstrated that the pharmacological stimulation of Nurr1 by amodiaquine (AQ) promotes spatial memory by enhancing adult hippocampal neurogenesis. However, the role of Nurr1 in the cell cycle regulation of the adult hippocampus has not been investigated. This study aimed to examine changes in the cell cycle-related molecules involved in adult hippocampal neurogenesis induced by Nurr1 pharmacological stimulation. Fluorescence-activated cell sorting (FACS) analysis showed that AQ improved the progression of cell cycle from G0/G1 to S phase in a dose-dependent manner, and MEK1 or PI3K inhibitors attenuated this progression. In addition, AQ treatment increased the expression of cell proliferation markers MCM5 and PCNA, and transcription factor E2F1. Furthermore, pharmacological stimulation of Nurr1 by AQ increased the expression levels of positive cell cycle regulators such as cyclin A and cyclin-dependent kinases (CDK) 2. In contrast, levels of CDK inhibitors p27KIP1 and p57KIP2 were reduced upon treatment with AQ. Similar to the in vitro results, RT-qPCR analysis of AQ-administered mice brains revealed an increase in the levels of markers of cell cycle progression, PCNA, MCM5, and Cdc25a. Finally, AQ administration resulted in decreased p27KIP1 and increased CDK2 levels in the dentate gyrus of the mouse hippocampus, as quantified immunohistochemically. Our results demonstrate that the pharmacological stimulation of Nurr1 in adult hNSCs by AQ promotes the cell cycle by modulating cell cycle-related molecules. Full article
(This article belongs to the Special Issue Mechanisms Linking Quiescence, Proliferation and Differentiation of Adult Stem Cells to Organismal Aging and Aging-Associated Diseases)
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Review

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8 pages, 626 KiB  
Review
The Use of Stem Cell Differentiation Stage Factors (SCDSFs) Taken from Zebrafish Embryos during Organogenesis and Their Role in Regulating the Gene Expression of Normal and Pathological (Stem) Cells
by Pier Mario Biava
Int. J. Mol. Sci. 2020, 21(14), 4914; https://doi.org/10.3390/ijms21144914 - 12 Jul 2020
Cited by 4 | Viewed by 3681
Abstract
Studies conducted on Zebrafish embryos in our laboratory have allowed for the identification of precise moments of organogenesis in which a lot of genes are switched on and off, a sign that the genome is undergoing substantial changes in gene expression. Stem cell [...] Read more.
Studies conducted on Zebrafish embryos in our laboratory have allowed for the identification of precise moments of organogenesis in which a lot of genes are switched on and off, a sign that the genome is undergoing substantial changes in gene expression. Stem cell growth and differentiation stage-factors present in different moments of organogenesis have proven to have different specific functions in gene regulation. The substances present in the first stages of cell differentiation in Zebrafish embryos have demonstrated an ability to counteract the senescence of stem cells, reducing the expression of the beta-galactosidase marker, enhancing the genes Oct-4, Sox-2, c-Myc, TERT, and the transcription of Bmi-1, which act as key telomerase-independent repressors of cell aging. The molecules present in the intermediate to late stages of cell differentiation have proven to be able to reprogram pathological human cells, such as cancer cells and those of the basal layer of the epidermis in psoriasis, which present a higher multiplication rate than normal cells. The factors present in all the stages of cell differentiation are able to counteract neurodegeneration, and to regenerate tissues: It has been possible to regenerate hair follicles in many patients with androgenetic alopecia through transdermal administration of stem cell differentiation stage factors (SCDSFs) by means of cryopass-laser. Full article
(This article belongs to the Special Issue Mechanisms Linking Quiescence, Proliferation and Differentiation of Adult Stem Cells to Organismal Aging and Aging-Associated Diseases)
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18 pages, 972 KiB  
Review
Regulation of Hematopoietic Stem Cell Fate and Malignancy
by Hee Jun Cho, Jungwoon Lee, Suk Ran Yoon, Hee Gu Lee and Haiyoung Jung
Int. J. Mol. Sci. 2020, 21(13), 4780; https://doi.org/10.3390/ijms21134780 - 6 Jul 2020
Cited by 11 | Viewed by 4772
Abstract
The regulation of hematopoietic stem cell (HSC) fate decision, whether they keep quiescence, self-renew, or differentiate into blood lineage cells, is critical for maintaining the immune system throughout one’s lifetime. As HSCs are exposed to age-related stress, they gradually lose their self-renewal and [...] Read more.
The regulation of hematopoietic stem cell (HSC) fate decision, whether they keep quiescence, self-renew, or differentiate into blood lineage cells, is critical for maintaining the immune system throughout one’s lifetime. As HSCs are exposed to age-related stress, they gradually lose their self-renewal and regenerative capacity. Recently, many reports have implicated signaling pathways in the regulation of HSC fate determination and malignancies under aging stress or pathophysiological conditions. In this review, we focus on the current understanding of signaling pathways that regulate HSC fate including quiescence, self-renewal, and differentiation during aging, and additionally introduce pharmacological approaches to rescue defects of HSC fate determination or hematopoietic malignancies by kinase signaling pathways. Full article
(This article belongs to the Special Issue Mechanisms Linking Quiescence, Proliferation and Differentiation of Adult Stem Cells to Organismal Aging and Aging-Associated Diseases)
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14 pages, 3696 KiB  
Review
Mechanisms that Link Chronological Aging to Cellular Quiescence in Budding Yeast
by Karamat Mohammad, Jennifer Anne Baratang Junio, Tala Tafakori, Emmanuel Orfanos and Vladimir I. Titorenko
Int. J. Mol. Sci. 2020, 21(13), 4717; https://doi.org/10.3390/ijms21134717 - 2 Jul 2020
Cited by 12 | Viewed by 3689
Abstract
After Saccharomyces cerevisiae cells cultured in a medium with glucose consume glucose, the sub-populations of quiescent and non-quiescent cells develop in the budding yeast culture. An age-related chronology of quiescent and non-quiescent yeast cells within this culture is discussed here. We also describe [...] Read more.
After Saccharomyces cerevisiae cells cultured in a medium with glucose consume glucose, the sub-populations of quiescent and non-quiescent cells develop in the budding yeast culture. An age-related chronology of quiescent and non-quiescent yeast cells within this culture is discussed here. We also describe various hallmarks of quiescent and non-quiescent yeast cells. A complex aging-associated program underlies cellular quiescence in budding yeast. This quiescence program includes a cascade of consecutive cellular events orchestrated by an intricate signaling network. We examine here how caloric restriction, a low-calorie diet that extends lifespan and healthspan in yeast and other eukaryotes, influences the cellular quiescence program in S. cerevisiae. One of the main objectives of this review is to stimulate an exploration of the mechanisms that link cellular quiescence to chronological aging of budding yeast. Yeast chronological aging is defined by the length of time during which a yeast cell remains viable after its growth and division are arrested, and it becomes quiescent. We propose a hypothesis on how caloric restriction can slow chronological aging of S. cerevisiae by altering the chronology and properties of quiescent cells. Our hypothesis posits that caloric restriction delays yeast chronological aging by targeting four different processes within quiescent cells. Full article
(This article belongs to the Special Issue Mechanisms Linking Quiescence, Proliferation and Differentiation of Adult Stem Cells to Organismal Aging and Aging-Associated Diseases)
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