Cytohesin 1 regulates homing and engraftment of human hematopoietic stem and progenitor cells.
Blood. 2017 Feb 23;129(8):950-958
Authors: Rak J, Foster K, Potrzebowska K, Talkhoncheh MS, Miharada N, Komorowska K, Torngren T, Kvist A, Borg Å, Svensson L, Bonnet D, Larsson J
Adhesion is a key component of hematopoietic stem cell regulation mediating homing and retention to the niche in the bone marrow. Here, using an RNA interference screen, we identify cytohesin 1 (CYTH1) as a critical mediator of adhesive properties in primary human cord blood-derived hematopoietic stem and progenitor cells (HSPCs). Knockdown of CYTH1 disrupted adhesion of HSPCs to primary human mesenchymal stroma cells. Attachment to fibronectin and ICAM1, 2 integrin ligands, was severely impaired, and CYTH1-deficient cells showed a reduced integrin β1 activation response, suggesting that CYTH1 mediates integrin-dependent functions. Transplantation of CYTH1-knockdown cells to immunodeficient mice resulted in significantly lower long-term engraftment levels, associated with a reduced capacity of the transplanted cells to home to the bone marrow. Intravital microscopy showed that CYTH1 deficiency profoundly affects HSPC mobility and localization within the marrow space and thereby impairs proper lodgment into the niche. Thus, CYTH1 is a novel major regulator of adhesion and engraftment in human HSPCs through mechanisms that, at least in part, involve the activation of integrins.
PMID: 27899358 [PubMed - indexed for MEDLINE]
Stem cell manipulation, gene therapy and the risk of cancer stem cell emergence.
Stem Cell Investig. 2017;4:67
Authors: Clément F, Grockowiak E, Zylbersztejn F, Fossard G, Gobert S, Maguer-Satta V
Stem cells (SCs) have been extensively studied in the context of regenerative medicine. Human hematopoietic stem cell (HSC)-based therapies have been applied to treat leukemic patients for decades. Handling of mesenchymal stem cells (MSCs) has also raised hopes and concerns in the field of tissue engineering. Lately, discovery of cell reprogramming by Yamanaka's team has profoundly modified research strategies and approaches in this domain. As we gain further insight into cell fate mechanisms and identification of key actors and parameters, this also raises issues as to the manipulation of SCs. These include the engraftment of manipulated cells and the potential predisposition of those cells to develop cancer. As a unique and pioneer model, the use of HSCs to provide new perspectives in the field of regenerative and curative medicine will be reviewed. We will also discuss the potential use of various SCs from embryonic to adult stem cells (ASCs), including induced pluripotent stem cells (iPSCs) as well as MSCs. Furthermore, to sensitize clinicians and researchers to unresolved issues in these new therapeutic approaches, we will highlight the risks associated with the manipulation of human SCs from embryonic or adult origins for each strategy presented.
PMID: 28815178 [PubMed]
Improved hematopoietic gene therapy in a mouse model of Fanconi anemia mediated by mesenchymal stromal cells.
Hum Gene Ther. 2017 Aug 17;:
Authors: Fernandez-Garcia M, Lamana Luzuriaga M, Hernando-Rodriguez M, Sanchez-Dominguez R, Bueren J, Yañez R
In this study we propose a novel approach based on the use of mesenchymal stromal cells (MSC) aiming at limiting risks of graft failure in gene therapy protocols associated with low conditioning regimens. Because the engraftment of corrected hematopoietic stem cells (HSCs) is particularly challenging in Fanconi anemia (FA), we have investigated the relevance of MSCs in an experimental model of FA gene therapy. Our results firstly showed that risks of graft failure in recipients conditioned with a moderate dose of 5Gy and infused with limited numbers of WT HSCs are significantly higher in Fanca-/- recipients as compared to WT recipients. However, when WT HSC numbers inducing 30-50% of graft failures in Fanca-/- recipients were co-infused with MSCs, no graft failures were observed. Moreover, graft failures associated to the infusion of low numbers of gene-corrected Fanca-/- HSCs were also significantly overcome by MSCs co-infusion. Our study shows for the first time that MSC co-infusion constitutes a simple and non-toxic approach to minimize risks of graft failure in gene-therapy applications associated with low conditioning regimens and infusion of limited numbers of corrected HSCs.
PMID: 28816065 [PubMed - as supplied by publisher]
Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion.
Leukemia. 2017 Aug 17;:
Authors: Kumar B, Garcia M, Weng L, Jung X, Murakami JL, Hu X, McDonald T, Lin A, Kumar AR, DiGiusto DL, Stein AS, Pullarkat VA, Hui SK, Carlesso N, Kuo YH, Bhatia R, Marcucci G, Chen CC
Little is known about how leukemia cells alter the bone marrow (BM) niche to facilitate their own growth and evade chemotherapy. Here, we provide evidence that acute myeloid leukemia (AML) blasts remodel the BM niche into a leukemia-growth-permissive and normal-hematopoiesis-suppressive microenvironment through exosome secretion. Either engrafted AML cells or AML-derived exosomes increased mesenchymal stromal progenitors and blocked osteolineage development and bone formation in vivo. Pre-conditioning with AML-derived exosomes 'primed' the animals for accelerated AML growth. Conversely, disruption of exosome secretion in AML cells through targeting Rab27a, an important regulator involved in exosome release, significantly delayed leukemia development. In BM stromal cells, AML-derived exosomes induced the expression of DKK1, a suppressor of normal hematopoiesis and osteogenesis, thereby contributing to osteoblast loss. Conversely, treatment with a DKK1 inhibitor delayed AML progression and prolonged survival in AML-engrafted mice. In addition, AML-derived exosomes induced a broad downregulation of hematopoietic stem cell supporting factors (e.g., CXCL12, KITL, and IGF1) in BM stromal cells and reduced their ability to support normal hematopoiesis. Altogether, this study uncovers novel features of AML pathogenesis and unveils how AML cells create a self-strengthening leukemic niche that promotes leukemic cell proliferation and survival, while suppressing normal hematopoiesis through exosome secretion.Leukemia accepted article preview online, 17 August 2017. doi:10.1038/leu.2017.259.
PMID: 28816238 [PubMed - as supplied by publisher]