Phenotypic and Functional Reversal Within the Early Human Hematopoietic Compartment

Knaän‐Shanzer, Shoshan; Dijke, Ietje van der Velde‐van; Watering, Marloes J.M. van de; Leeuw, Philip J. de; Valerio, D.; Bekkum, D. W. van; Vries, Antoine A.F. de

doi:10.1634/stemcells.2007-0117

Cited by 15 publications

(12 citation statements)

References 44 publications

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“…Our data show that there was no observed toxicity on this population of cells. This is consistent with the fact that these non-committed progenitors express very low levels of the TfR1/CD71 (Gross et al 1997; Knaan-Shanzer et al 2008; Lansdorp and Dragowska 1992). We have previously shown that the conjugate is toxic to late (committed) progenitor cells of both the erythroid and myeloid lineages (CFU-e, BFU-e and CFU-GM) (Daniels et al 2011) that are known to express the TfR1 (Daniels et al 2006b).…”

Section: Discussionsupporting

confidence: 87%

Insights into the mechanism of cell death induced by saporin delivered into cancer cells by an antibody fusion protein targeting the transferrin receptor 1

Daniels‐Wells

Helguera

Rodríguez

et al. 2013

Toxicology in Vitro

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We previously developed an antibody-avidin fusion protein (ch128.1Av) that targets the human transferrin receptor 1 (TfR1) and exhibits direct cytotoxicity against malignant B cells in an iron-dependent manner. ch128.1Av is also a delivery system and its conjugation with biotinylated saporin (b-SO6), a plant ribosome-inactivating toxin, results in a dramatic iron-independent cytotoxicity, both in malignant cells that are sensitive or resistant to ch128.1Av alone, in which the toxin effectively inhibits protein synthesis and triggers caspase activation. We have now found that the ch128.1Av/b-SO6 complex induces a transcriptional response consistent with oxidative stress and DNA damage, a response that is not observed with ch128.1Av alone. Furthermore, we show that the antioxidant N-acetylcysteine partially blocks saporin-induced apoptosis suggesting that oxidative stress contributes to DNA damage and ultimately saporin-induced cell death. Interestingly, the toxin was detected in nuclear extracts by immunoblotting, suggesting the possibility that saporin might induce direct DNA damage. However, confocal microscopy did not show a clear and consistent pattern of intranuclear localization. Finally, using the long-term culture-initiating cell assay we found that ch128.1Av/b-SO6 is not toxic to normal human hematopoietic stem cells suggesting that this critical cell population would be preserved in therapeutic interventions using this immunotoxin.

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Section: Discussionsupporting

confidence: 87%

Insights into the mechanism of cell death induced by saporin delivered into cancer cells by an antibody fusion protein targeting the transferrin receptor 1

Daniels‐Wells

Helguera

Rodríguez

et al. 2013

Toxicology in Vitro

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“…This colony was established with mice originally purchased from Jackson Laboratories (Bar Harbor, Me., USA). The mice were kept and housed as previously described [25]. All experimental procedures were approved by the local Experimental Animal Ethics Committee.…”

Section: Methodsmentioning

confidence: 99%

Pressure Ulcers: Description of a New Model and Use of Mesenchymal Stem Cells for Repair

Garza-Rodea

Knaän‐Shanzer

Bekkum³

2011

Dermatology

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Background: Pressure ulcers (PUs) still represent a heavy burden on many patients and nursing institutions. Our understanding of the pathophysiology and development of new treatments are hampered by the scarcity of suitable animal models. Objective: Evaluation of the translational value of an easily accessible mouse model. Methods: PUs were induced by application of magnetic devices on the dorsal skin of mice, which causes localized ischemia. The extent of the lesions and healing rate were quantified. Variations in ischemic exposure time were compared in hairless and normal mice. A detailed histological analysis of regeneration is presented. The influence of streptozotocin-induced diabetes, skin X-irradiation and treatment of the ulcers with human mesenchymal stem cells (MSCs) was investigated using immunodeficient NOD/SCID mice. Results: Ulcers induced by this form of ischemia have many features in common with decubitus ulcers in humans. No difference between hairy and hairless mice was observed in the rate of healing of the PUs. Unexpectedly, healing was not delayed in diabetic mice, but skin X-irradiation prior to ischemia resulted in a doubling of the time to complete closure of the PUs, and delayed repair of the dermis and panniculus carnosus muscle. Intradermal transplantation of human MSCs did not accelerate healing. The grafted MSCs were short-lived and only marginally participated in regeneration by differentiating into tissue-specific cells. Conclusion: The results emphasize the difference in the characteristics of PUs as compared to surgical wounds. This experimental model is recommended for preclinical research on decubitus ulcers because of its mechanistic similarity with clinical PUs and its simplicity.

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“…Importantly, the higher the expression of CD34 in a given HSPC subset is, the higher its efficacy both in an in vivo long‐term re‐populating assay (Krause et al ., ) and in clinical BM transplantation outcome (Beksac and Preffer, ). This can be explained either as the occurrence of a specific stem cell subpopulation within the CD34 high ‐HSPC pool or as a higher propensity of CD34 high ‐HSPC to reverse their pre‐commitment thereby recovering features of multipotent stem cells (Dooner et al ., ; Knaän‐Shanzer et al ., ; Puca et al ., ).…”

Section: Introductionmentioning

confidence: 99%

To breathe or not to breathe: the haematopoietic stem/progenitor cells dilemma

Piccoli

Agriesti

Scrima

et al. 2013

British J Pharmacology

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Adult haematopoietic stem/progenitor cells (HSPCs) constitute the lifespan reserve for the generation of all the cellular lineages in the blood. Although massive progress in identifying the cluster of master genes controlling self-renewal and multipotency has been achieved in the past decade, some aspects of the physiology of HSPCs still need to be clarified. In particular, there is growing interest in the metabolic profile of HSPCs in view of their emerging role as determinants of cell fate. Indeed, stem cells and progenitors have distinct metabolic profiles, and the transition from stem to progenitor cell corresponds to a critical metabolic change, from glycolysis to oxidative phosphorylation. In this review, we summarize evidence, reported in the literature and provided by our group, highlighting the peculiar ability of HSPCs to adapt their mitochondrial oxidative/ bioenergetic metabolism to survive in the hypoxic microenvironment of the endoblastic niche and to exploit redox signalling in controlling the balance between quiescence versus active cycling and differentiation. Especial prominence is given to the interplay between hypoxia inducible factor-1, globins and NADPH oxidases in managing the mitochondrial dioxygen-related metabolism and biogenesis in HSPCs under different ambient conditions. A mechanistic model is proposed whereby 'mitochondrial differentiation' is a prerequisite in uncommitted stem cells, paving the way for growth/differentiation factor-dependent processes. Advancing the understanding of stem cell metabolism will, hopefully, help to (i) improve efforts to maintain, expand and manipulate HSPCs ex vivo and realize their potential therapeutic benefits in regenerative medicine; (ii) reprogramme somatic cells to generate stem cells; and (iii) eliminate, selectively, malignant stem cells. LINKED ARTICLESThis article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2013.169.issue-8 Abbreviations AMPK, AMP-activated PK; BM, bone marrow; FAO, fatty acid oxidation; HIF-1, hypoxia inducible factor-1; HRE, hypoxia response elements; HSC, haematopoietic stem cell; HSPC, haematopoietic stem/progenitor cell; Lkb1, liver kinase B1; LT-HSC, long-term HSC; OXPHOS, mitochondrial oxidative phosphorylation; NOX, NADPH oxidase; PGC-1α, PPARγ co-activator 1α ; PML, promyelocytic leukaemia; RC, respiratory chain IntroductionThe mammalian blood system comprises an array of cell types, including erythrocytes, myeloid cells, megakaryocytes and platelets, lymphocytes, natural killer cells, dendritic cells and mast cells. As diverse as these cells are, they all originate from haematopoietic stem cells (HSCs), which are a limited pool of immature progenitors residing in the bone marrow (BM). A reservoir of long-term HSCs (LT-HSCs) lies at the very top of the cellular hierarchy. LT-HSCs guarantee a continuous supply of blood cells throughout an individual's lifetime due to their potential to self-renew (give ris...

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Phenotypic and Functional Reversal Within the Early Human Hematopoietic Compartment

Abstract: ABSTRACT

Cited by 15 publications

References 44 publications

Insights into the mechanism of cell death induced by saporin delivered into cancer cells by an antibody fusion protein targeting the transferrin receptor 1

Insights into the mechanism of cell death induced by saporin delivered into cancer cells by an antibody fusion protein targeting the transferrin receptor 1

Pressure Ulcers: Description of a New Model and Use of Mesenchymal Stem Cells for Repair

To breathe or not to breathe: the haematopoietic stem/progenitor cells dilemma

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