scholarly journals Antioxidant Levels Represent a Major Determinant in the Regenerative Capacity of Muscle Stem Cells

2009 ◽  
Vol 20 (1) ◽  
pp. 509-520 ◽  
Author(s):  
Kenneth L. Urish ◽  
Joseph B. Vella ◽  
Masaho Okada ◽  
Bridget M. Deasy ◽  
Kimimasa Tobita ◽  
...  
Keyword(s):  
Stem Cells ◽  
Antioxidant Capacity ◽  
Functional Characteristic ◽  
Post Transplantation ◽  
Regenerative Capacity ◽  
Inflammatory Stress ◽  
Muscle Stem Cells ◽  
Cardiac Muscles

Stem cells are classically defined by their multipotent, long-term proliferation, and self-renewal capabilities. Here, we show that increased antioxidant capacity represents an additional functional characteristic of muscle-derived stem cells (MDSCs). Seeking to understand the superior regenerative capacity of MDSCs compared with myoblasts in cardiac and skeletal muscle transplantation, our group hypothesized that survival of the oxidative and inflammatory stress inherent to transplantation may play an important role. Evidence of increased enzymatic and nonenzymatic antioxidant capacity of MDSCs were observed in terms of higher levels of superoxide dismutase and glutathione, which appears to confer a differentiation and survival advantage. Further when glutathione levels of the MDSCs are lowered to that of myoblasts, the transplantation advantage of MDSCs over myoblasts is lost when transplanted into both skeletal and cardiac muscles. These findings elucidate an important cause for the superior regenerative capacity of MDSCs, and provide functional evidence for the emerging role of antioxidant capacity as a critical property for MDSC survival post-transplantation.

scholarly journals Hematopoietic stem cells fail to regenerate following inflammatory challenge

2020 ◽  
Author(s):  
Ruzhica Bogeska ◽  
Paul Kaschutnig ◽  
Malak Fawaz ◽  
Ana-Matea Mikecin ◽  
Marleen Büchler-Schäff ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Recovery Period ◽  
Cumulative Impact ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Inflammatory Stress ◽  
Kinetics Of

AbstractHematopoietic stem cells (HSCs) are canonically defined by their capacity to maintain the HSC pool via self-renewal divisions. However, accumulating evidence suggests that HSC function is instead preserved by sustaining long-term quiescence. Here, we study the kinetics of HSC recovery in mice, following an inflammatory challenge that induces HSCs to exit dormancy. Repeated inflammatory challenge resulted in a progressive depletion of functional HSCs, with no sign of later recovery. Underlying this observation, label retention experiments demonstrated that self-renewal divisions were absent or extremely rare during challenge, as well as during any subsequent recovery period. While depletion of functional HSCs held no immediate consequences, young mice exposed to inflammatory challenge developed blood and bone marrow hypocellularity in old age, similar to elderly humans. The progressive, irreversible attrition of HSC function demonstrates that discreet instances of inflammatory stress can have an irreversible and therefore cumulative impact on HSC function, even when separated by several months. These findings have important implications for our understanding of the role of inflammation as a mediator of dysfunctional tissue maintenance and regeneration during ageing.

scholarly journals Ing4-deficiency enhances HSC quiescence and confers resistance to inflammatory stress

2021 ◽  
Author(s):  
Zanshé Thompson ◽  
Georgina A. Anderson ◽  
Melanie Rodriguez ◽  
Seth Gabriel ◽  
Vera Binder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Malignant Cells ◽  
Short Term ◽  
Regenerative Capacity ◽  
Hematopoietic Stem ◽  
Inflammatory Stress ◽  
Identification And Characterization

Hematopoiesis is tightly regulated by a network of transcription factors and complexes that are required for the development and maintenance of hematopoietic stem cells (HSCs). We recently identified the tumor suppressor, Ing4, as a critical regulator of HSC homeostasis. Though the Ing4 mechanism of action remains poorly characterized, it has been shown to promote stem-like cell characteristics in malignant cells. This activity is, in part, due to Ing4 mediated regulation of several major signaling pathways, including NF-kB and c-Myc. In murine hematopoiesis, Ing4 deficiency induces G0 arrest in HSCs, while simultaneously promoting gene expression signatures associated with differentiation. This results in a poised state for Ing4-deficient HSCs. Long term HSCs are unable to overcome this block, but short-term HSCs convert the poised state into regenerative capacity during hematopoietic challenges, including irradiation and transplantation. Overall, our findings suggest that Ing4 plays a crucial role in the regulation of hematopoiesis. Our model provides key tools for further identification and characterization of pathways that control quiescence and differentiation in HSCs.

scholarly journals Role of satellite cells in growth and regeneration of skeletal muscles

2019 ◽  
Vol 75 (11) ◽  
pp. 6349-2019 ◽  
Author(s):  
ANNA CIECIERSKA ◽  
TOMASZ SADKOWSKI ◽  
TOMASZ MOTYL
Keyword(s):  
Stem Cells ◽  
Satellite Cells ◽  
Skeletal Muscles ◽  
Postnatal Growth ◽  
Regeneration Capacity ◽  
Regenerative Capacity ◽  
Self Renewal ◽  
Muscle Stem Cells ◽  
Cell Pool

Postnatal growth and regeneration capacity of skeletal muscles is dependent mainly on adult muscle stem cells called satellite cells. Satellite cells are quiescent mononucleated cells that are normally located outside the sarcolemma within the basal lamina of the muscle fiber. Their activation, which results from injury, is manifested by mobilization, proliferation, differentiation and, ultimately, fusion into new muscle fibers. The satellite cell pool is responsible for the remarkable regenerative capacity of skeletal muscles. Moreover, these cells are capable of self-renewal and can give rise to myogenic progeny.

scholarly journals CXCR4-SDF-1 Signaling in Nestin+ Mesenchymal Stem Cell Is Required for HSC Maintenance during Homeostasis and Regeneration after Irradiation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3883-3883 ◽  
Author(s):  
Pratibha Singh ◽  
Louis M. Pelus
Keyword(s):  
Stem Cells ◽  
Stromal Cell ◽  
Cxcr4 Expression ◽  
Wild Type ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Cxcr4 Signaling ◽  
Hematopoietic Recovery ◽  
Hematopoietic Reconstitution

Hematopoietic stem cells (HSC) reside in a complex microenvironment (niche) within the bone marrow (BM), where multiple populations of microenvironmental stromal cells regulate and finely tune their proliferation, differentiation and trafficking. Recent studies have shown that mesenchymal stem cells (MSC) are an essential component of the HSC niche. Intrinsic HSC CXCR4-SDF-1 signaling has been implicated in self-renewal and quiescence; however, the role of microenvironment CXCR4-SDF-1 signaling in supporting HSC function remains unclear. We previously demonstrated that microenvironmental stromal cell-derived CXCR4 is important for HSC recovery, as transplantation of wild-type HSC into CXCR4 deficient recipients showed reduced HSC engraftment. In this study, we now show that CXCR4-SDF-1 signaling in nestin+ MSC regulates HSC maintenance under normal homeostatic conditions and promotes hematopoietic regeneration after irradiation. Multivariate flow cytometry analysis of marrow stroma cells revealed that mouse BM MSCs identified as CD45-Ter119-CD31-Nestin+PDGFR+CD51+ express the CXCR4 receptor, which was confirmed by RT-PCR analysis. To investigate the role of MSC CXCR4 signaling in niche maintenance and support of HSC function, we utilized genetic mouse models, in which CXCR4 could be deleted in specific stromal cell types. Selective deletion of CXCR4 from nestin+ MSC in adult tamoxifen inducible nestin-cre CXCR4flox/flox mice resulted in reduced total MSC in BM (Control vs. Deleted: 647±128 vs. 209±51/femur, respectively, n=5, p<0.05), which was associated with a significant reduction in Lineage-Sca-1+c-Kit+ (LSK) cells (Control vs. Deleted: 18,033±439 vs. 4523±358/femur, respectively n=5, p<0.05). Selective CXCR4 deletion in nestin+ MSC also resulted in enhanced LSK cell egress to the peripheral circulation (Control vs. Deleted: 1022±106 vs. 2690±757/ml blood, respectively n=5, p<0.05), with no detectable difference in HSC cell cycle or apoptosis. However, the repopulation ability of HSC obtained from mice where CXCR4 was deleted in nestin+ MSC was reduced by >2 fold. In contrast, deletion of CXCR4 from osteoblasts using osteocalcin cre CXCR4flox/flox mice had no effect on HSC numbers in BM and blood.To investigate the role of nestin+ MSC CXCR4 signaling in BM niche reconstruction and hematopoietic recovery, we transplanted BM cells from wild-type mice into syngeneic wild-type or nestin+ MSC CXCR4 deleted recipients after lethal irradiation (950 rad) and analyzed HSC homing, niche recovery and hematopoietic reconstitution. Deletion of CXCR4 from nestin expressing MSC resulted in significantly reduced LSK cell homing at 16 hrs post transplantation (Control vs. Deleted: 8643±1371 vs. 3004±1044/ mouse, respectively, n=5, p<0.05). Robust apoptosis and senescence after total body irradiation was observed in nestin expressing MSCs lacking CXCR4 expression. At 15 days post-transplantation, chimeric mice with nestin+ MSC lacking CXCR4 expression displayed attenuated niche recovery and hematopoietic reconstitution compared to mice with wild-type stroma. In conclusion, our study suggests that CXCR4-SDF-1 signaling in nestin+ MSC is critical for the maintenance and retention of HSC in BM during homeostasis and promotes niche regeneration and hematopoietic recovery after transplantation. Furthermore, our data suggest the modulating CXCR4 signaling in the hematopoietic niche could be beneficial as a means to enhance HSC recovery following clinical hematopoietic transplantation or radiation/chemotherapy injury. Disclosures No relevant conflicts of interest to declare.

scholarly journals Uterus transplantation: joys and frustrations of becoming a ‘complete’ woman—a qualitative study regarding self-image in the 5-year period after transplantation

2020 ◽  
Vol 35 (8) ◽  
pp. 1855-1863 ◽  
Author(s):  
Stina Järvholm ◽  
Anders Enskog ◽  
Catrina Hammarling ◽  
Pernilla Dahm-Kähler ◽  
Mats Brännström
Keyword(s):  
Small Sample Size ◽  
Small Sample ◽  
Post Transplantation ◽  
Uterus Transplantation ◽  
Self Image ◽  
Registration Number ◽  
Competing Interest ◽  
The Government

Abstract STUDY QUESTION How is a women’s self-image affected by uterus transplantation (UTx)? SUMMARY ANSWER Women experienced receiving a uterus in both positive and negative ways, but in general, their self-image was positively affected; regardless of whether they have given birth to a child or not, recipients describe themselves as being ‘back to normal’ after the hysterectomy to remove the transplanted uterus. WHAT IS KNOWN ALREADY UTx has repeatedly proved to be a successful treatment for absolute uterine factor infertility. However, there has been no previous qualitative long-term research into the self-image of women undergoing UTx. STUDY DESIGN, SIZE, DURATION This complete, prospective cohort study included the nine recipients of the first UTxs performed in Sweden mostly in 2013. Interviews took place in the 5 years following surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS Eight out of the nine recipients had congenital absence of the uterus, a characteristic of Mayer–Rokitansky–Küster–Hauser syndrome, and one recipient lacked a uterus after a radical hysterectomy due to cervical cancer. The mean age of participants was 31.5 years at inclusion and at this time they all lived in stable marital relationships. Post-transplantation, interviews were performed annually for 5 years, comprising a total of 43 interviews. The interview followed a semi-structured guide. All interviews (median duration of around 25 minutes) were recorded, transcribed verbatim and then analysed by thematic approach. MAIN RESULTS AND THE ROLE OF CHANCE The joys and frustrations of becoming a ‘complete’ woman are seen as a master theme, which influences the three underlying subthemes, a changed self-perception, a changed body and a changed sexuality. Each of these subthemes have three underlying categories. LIMITATIONS, REASONS FOR CAUTION The small sample size is a limitation. WIDER IMPLICATIONS OF THE FINDINGS The results provide information that will be helpful in pre-operative screening procedures and in the psychological support offered both to women who experienced successful and unsuccessful outcomes following UTx. STUDY FUNDING/COMPETING INTEREST(S) Funding was received from the Jane and Dan Olsson Foundation for Science; the Knut and Alice Wallenberg Foundation; an ALF grant from the Swedish state under an agreement between the government and the county councils; the Swedish Research Council; a Ferring Pharmaceuticals scholarship in memory of Robert Edwards; and the Iris Jonzén-Sandblom and Greta Jonzén Foundation. The authors have no competing interests. TRIAL REGISTRATION NUMBER NCT01844362.

scholarly journals Enzymatic treatment of long-term human marrow cultures reveals the preferential location of primitive hemopoietic progenitors in the adherent layer

Blood ◽  
1983 ◽  
Vol 62 (2) ◽  
pp. 291-297 ◽  
Author(s):  
L Coulombel ◽  
AC Eaves ◽  
CJ Eaves
Keyword(s):  
Stem Cells ◽  
Marrow Cell ◽  
Point Of View ◽  
Adherent Cell ◽  
Reproducible Method ◽  
Preferential Location ◽  
Very High ◽  
Marrow Cultures

Abstract Recent studies with long-term mouse marrow cultures have indicated the importance of the adherent layer as a primary reservoir of the most primitive stem cells, from which derivative stem cells and more differentiated progenitors are continuously generated. We have now examined the role of the adherent cell layer in long-term human marrow cultures from this point of view. Prerequisite to such an undertaking was the development of a nontoxic and reproducible method for detaching the adherent layer and making it into a single-cell suspension suitable for characterization by colony assays. Both trypsin and collagenase could be used to obtain suspensions that met these criteria. Lack of toxicity was demonstrated by the preservation of CFU-E, BFU-E, and CFU- C plating efficiency in fresh human marrow cell suspensions exposed to the same enzymatic treatments. Collagenase treatment of long-term marrow culture adherent layers was considered superior because it freed all hemopoietic colony-forming cells but left some of the other cells still adherent. Using this method, we found that CFU-C, BFU-E, and CFU- G/E were consistently detectable in the adherent layer for at least 8 wk, with the majority of the BFU-E and CFU-G/E being located in the adherent layer (70%-75% after 2–3 wk and more than 90% by 7–8 wk). Although corresponding numerical differences in adherent and nonadherent CFU-C populations were not observed, the colonies derived from them showed marked differences in the size they achieved; the adherent layer being the exclusive site of CFU-C, with a very high proliferative capacity. These findings emphasize the importance of assessing the progenitor content of the adherent layer of long-term human marrow cultures and provide an appropriate methodology.

scholarly journals Circulating stem cells and cardiovascular outcomes: from basic science to the clinic

2019 ◽  
Vol 41 (44) ◽  
pp. 4271-4282 ◽  
Author(s):  
Gian Paolo Fadini ◽  
Anurag Mehta ◽  
Devinder Singh Dhindsa ◽  
Benedetta Maria Bonora ◽  
Gopalkrishna Sreejit ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cardiovascular Outcomes ◽  
Background Information ◽  
Regenerative Capacity ◽  
Cell Therapies ◽  
Clinical Biomarkers ◽  
Health And Disease ◽  
Adult Organism ◽  
Physiologic Role

Abstract The cardiovascular and haematopoietic systems have fundamental inter-relationships during development, as well as in health and disease of the adult organism. Although haematopoietic stem cells (HSCs) emerge from a specialized haemogenic endothelium in the embryo, persistence of haemangioblasts in adulthood is debated. Rather, the vast majority of circulating stem cells (CSCs) is composed of bone marrow-derived HSCs and the downstream haematopoietic stem/progenitors (HSPCs). A fraction of these cells, known as endothelial progenitor cells (EPCs), has endothelial specification and vascular tropism. In general, the levels of HSCs, HSPCs, and EPCs are considered indicative of the endogenous regenerative capacity of the organism as a whole and, particularly, of the cardiovascular system. In the last two decades, the research on CSCs has focused on their physiologic role in tissue/organ homoeostasis, their potential application in cell therapies, and their use as clinical biomarkers. In this review, we provide background information on the biology of CSCs and discuss in detail the clinical implications of changing CSC levels in patients with cardiovascular risk factors or established cardiovascular disease. Of particular interest is the mounting evidence available in the literature on the close relationships between reduced levels of CSCs and adverse cardiovascular outcomes in different cohorts of patients. We also discuss potential mechanisms that explain this association. Beyond CSCs’ ability to participate in cardiovascular repair, levels of CSCs need to be interpreted in the context of the broader connections between haematopoiesis and cardiovascular function, including the role of clonal haematopoiesis and inflammatory myelopoiesis.

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