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Endothelial cell-HSC interactions during homing and engraftment. During development and transplantation HSCs must home to, and engraft in, the stem cell niche. a Definitive hematopoiesis is initiated when HSCs are specified from hemogenic endothelium in the aorta-gonad-mesonephros (AGM) region. HSCs bud from the ventral wall of the dorsal aorta, enter circulation, and home to the fetal liver. After extravasating into the fetal niche, ECs remodel around the HSC in a process termed “endothelial cell cuddling.” HSCs expand in the fetal niche and then home to, and engraft in, the adult niche in the bone marrow. HSCs engraft in complex and specialized niches consisting of multiple specialized cell types. These niches maintain HSCs and regulate their self-renewal and differentiation into all mature blood lineages. b HSCs undergo a series of stereotyped actions to home towards the niche, all of which depend on endothelial cells—rolling, arrest and firm adhesion, spreading, and extravasation. Rolling is initiated when E- and P-selectin receptors on ECs tether to their ligands on the HSC, serving as a molecular brake to slow HSC migration in circulation. Chemokine CXCL12 then activates VCAM and ICAM adhesion molecules, which promote firm adhesion of HSCs to vascular ECs. Finally, chemokines and adhesion molecules direct polarized migration across the endothelium and result in HSC extravasation
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Cells of the hematopoietic system undergo rapid turnover. Each day, humans require the production of about one hundred billion new blood cells for proper function. Hematopoietic stem cells (HSCs) are rare cells that reside in specialized niches and are required throughout life to produce specific progenitor cells that will replenish all blood linea...
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... ,B). Such temporal changes in adhesion dynamics during CS13CS14 might underlie cell transitions and movements during EHT, including such processes as the potential rolling Development • Accepted manuscript of HSPCs along the Ao endothelium and trans-endothelial monocyte/macrophage migration(Perlin et al., 2017;Mariani et al., 2019). Notably, PROC (Protein C), has predicted interactions with its 3 receptors PROCR (EPCR), THBD and TEK within CS14_VI. ...
The emergence of definitive human haematopoietic stem cells (HSCs) during Carnegie Stages (CS) 14-17 in the aorta-gonad-mesonephros (AGM) region is a tightly regulated process. Previously, we conducted spatial transcriptomic analysis of the human AGM region at the end of this period (CS16/17) and identified secreted factors involved in HSC development. Here, we extend our analysis to investigate the progression of dorso-ventral polarized signalling around the dorsal aorta over the entire period of HSC emergence. Our results reveal a dramatic increase in ventral signalling complexity from the CS13 to CS14 transition, coinciding with the first appearance of definitive HSCs. We further observe stage-specific changes in signalling up to CS17 which may underpin the step-wise maturation of HSCs described in the mouse model. The data-rich resource is also presented in an online interface enabling in silico analysis of molecular interactions between spatially defined domains of the AGM region. This resource will be of particular interest for researchers studying mechanisms underlying human HSC development as well as those developing in vitro methods for the generation of clinically relevant HSCs from pluripotent stem cells.
... Hematopoietic stem and progenitor cells (HSPCs) are a rare population of cells capable of reconstituting the entire blood system. 1 In the bone marrow, multiple cell types are thought to contribute to the HSPC niche, with endothelial cells (ECs) being a primary component. [2][3][4][5][6][7] Distinct endothelial subtypes differentially regulate HSPCs: arterial ECs (AECs) promote HSPC quiescence, whereas sinusoidal ECs (SECs) support HSPC differentiation and mobilization. 8-10 Specialized bone marrow ECs play a critical role in niche reconstruction and hematopoietic recovery after myelosuppression, 11,12 and ECs support HSPCs outside the bone marrow during development and stress-induced hematopoiesis. ...
The hematopoietic niche is a supportive microenvironment composed of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses in zebrafish, we define a conserved gene expression signature and cis-regulatory landscape that are unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code that involves members of the Ets, Sox, and nuclear hormone receptor families and is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance, and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.
... Different cell types have been identified in proximity to murine HSCs in vivo, including endosteal osteoblasts, sinusoidal ECs, leptin receptor-positive (Lepr+) perivascular stromal cells, CXCL12 high reticular cells, nestin+ mesenchymal stem cells, non-myelinating Schwann cells, regulatory T cells and megakaryocytes (Kumar and Geiger, 2017;Perlin et al., 2017), which secrete growth factors and cytokines that regulate HSC quiescence, homing and differentiation. For example, osteoblasts Frontiers in Genome Editing frontiersin.org ...
... For example, osteoblasts Frontiers in Genome Editing frontiersin.org secrete a variety of cytokines, including osteopontin, angiopietin-1 and -3, thrombopoietin, granulocyte colony-stimulating factor, stem-cell factor (SCF) and SDF-1 (Kumar and Geiger, 2017;Perlin et al., 2017), which regulate HSC self-renewal and homing. Homing and engraftment of intravenously administered HSCs via the blood to the BM HSC niche is enforced by HSC-attracting chemotactic and other bioactive molecules released in the BM microenvironment (Heazlewood et al., 2014;Ratajczak and Suszynska, 2016). ...
... The chemotactic factors include SDF-1 and SCF (Peled et al., 2000;Xu et al., 2018). Endothelial and stromal cells are an important source of SDF-1 and SCF, which promote HSC maintenance and localization to the perivascular BM niche (Kumar and Geiger, 2017;Perlin et al., 2017). For example, Tie2-Cre-mediated inactivation of SDF-1 and SCF in ECs leads to HSCs depletion in the BM niche (Kisanuki et al., 2001;Sipkins et al., 2005;Greenbaum et al., 2013;Morrison and Scadden, 2014). ...
Modern-day hematopoietic stem cell (HSC) therapies, such as gene therapy, modify autologous HSCs prior to re-infusion into myelo-conditioned patients and hold great promise for treatment of hematological disorders. While this approach has been successful in numerous clinical trials, it relies on transplantation of ex vivo modified patient HSCs, which presents several limitations. It is a costly and time-consuming procedure, which includes only few patients so far, and ex vivo culturing negatively impacts on the viability and stem cell-properties of HSCs. If viral vectors are used, this carries the additional risk of insertional mutagenesis. A therapy delivered to HSCs in vivo, with minimal disturbance of the HSC niche, could offer great opportunities for novel treatments that aim to reverse disease symptoms for hematopoietic disorders and could bring safe, effective and affordable genetic therapies to all parts of the world. However, substantial unmet needs exist with respect to the in vivo delivery of therapeutics to HSCs. In the last decade, in particular with the development of gene editing technologies such as CRISPR/Cas9, nanoparticles (NPs) have become an emerging platform to facilitate the manipulation of cells and organs. By employing surface modification strategies, different types of NPs can be designed to target specific tissues and cell types in vivo. HSCs are particularly difficult to target due to the lack of unique cell surface markers that can be utilized for cell-specific delivery of therapeutics, and their shielded localization in the bone marrow (BM). Recent advances in NP technology and genetic engineering have resulted in the development of advanced nanocarriers that can deliver therapeutics and imaging agents to hematopoietic stem- and progenitor cells (HSPCs) in the BM niche. In this review we provide a comprehensive overview of NP-based approaches targeting HSPCs to control and monitor HSPC activity in vitro and in vivo, and we discuss the potential of NPs for the treatment of malignant and non-malignant hematological disorders, with a specific focus on the delivery of gene editing tools.
... The sinusoidal vessels are more permeable than the arteriolar ones, so HSCs maintained in this niche have a greater level of reactive oxygen species (ROS) and as such, are more activated (86). Additionally, sinusoidal ECs express higher levels of E-selectin which plays a key role in HSC homing and proliferation (89). Endothelial cytokines such as SCF, CXC12, and JAGGED-1 are also implicated in sinusoidal HSC maintenance, though the relative contributions of SCF and CXC12 from ECs is small in comparison with the contribution from mesenchymal progenitor cells (80,86,90). ...
... The HSCs maintained in the arteriolar niche are mostly quiescent, due in part to the low levels of ROS which promotes self-renewal. Arteriolar ECs have higher expression levels of vascular cell adhesion molecule-1 (VCAM-1) which has been associated with HSC retention (79,89). Though these two niches are thought of as distinct, it has been demonstrated that within the sinusoidal niche both quiescent ROS low HSCs and proliferating ROS high HSCs are present (91). ...
Cancer stem cells are thought to be the main drivers of tumorigenesis for malignancies such as glioblastoma (GBM). They are maintained through a close relationship with the tumor vasculature. Previous literature has well-characterized the components and signaling pathways for maintenance of this stem cell niche, but details on how the niche initially forms are limited. This review discusses development of the nonmalignant neural and hematopoietic stem cell niches in order to draw important parallels to the malignant environment. We then discuss what is known about the cancer stem cell niche, its relationship with angiogenesis, and provide a hypothesis for its development in GBM. A better understanding of the mechanisms of development of the tumor stem cell niche may provide new insights to potentially therapeutically exploit.
... Located in the perivascular compartment of the BM cavity, endothelial cells regulate multilineage hematopoiesis through the secretion of soluble factors and protect vascular integrity against inflammatory insults [97][98][99]. Many studies have collectively portrayed endothelial cells as angiogenic facilitators, hence promoting leukemogenesis, but characterization of such leukemogenicity through the lens of LSCs remains insufficient [100][101][102]. ...
Notoriously known for their capacity to reconstitute hematological malignancies in vivo, leukemic stem cells (LSCs) represent key drivers of therapeutic resistance and disease relapse, posing as a major medical dilemma. Despite having low abundance in the bulk leukemic population, LSCs have developed unique molecular dependencies and intricate signaling networks to enable self-renewal, quiescence, and drug resistance. To illustrate the multi-dimensional landscape of LSC-mediated leukemogenesis, in this review, we present phenotypical characteristics of LSCs, address the LSC-associated leukemic stromal microenvironment, highlight molecular aberrations that occur in the transcriptome, epigenome, proteome, and metabolome of LSCs, and showcase promising novel therapeutic strategies that potentially target the molecular vulnerabilities of LSCs.
... These data indicate a critical role of the β1 integrin family, especially of α4 (α4β1 or VLA4) in HPSC homing steps, including rolling through trans-endothelium, BM luminal localization, and even firm adherence of these cells, though not adequate studies have been performed to clarify the role of other VLAs including VLA5 and VLA6 in HPSCs homing. Based on the literature, it has been found that in contrast to selectins, which are restricted to get involved in the initial stage of HPSCs homing (endothelium rolling), VLAs seems to play a continuous role in all stages of this phenomenon, including rolling through primary endothelium, firm adhesion, intramedullary migration, and niche adhesion [16][17][18]. Thus, in this regard, this study is aimed to investigate the correlation between the expression level of VLA4, VLA5, VLA6 and PSGL1 genes and engraftment time of HPSCs in MM candidate patients for autologous bone marrow transplantation. ...
The most promising therapy for leukemia is hematopoietic stem cell transplantation. Engraftment of HPSCs mainly depends on some factors such as adhesion molecules, including VLAs. This study tried to delineate the relationship between HPSCs engraftment and expression level of PSGL1 and VLA4, 5, and 6 genes in candidate MM patients for autologous bone marrow transplantation. Firstly, the CD 34+ HPSCs were collected from multiple myeloma (MM) patients after five days of G-CSF therapy through apheresis processes. Then, the patients were categorized into two groups of good and bad prognosis depending on engraftment time (Less or more than 18 days). Followingly, the expression of PSGL1 and VLA4, VLA5, and VLA6 genes were assessed by the qRT-PCR technique in each patient. Finally, the correlation between the genes and engraftment time was investigated to determine the prognostic role of each gene on HPSCs transplantation. Our findings demonstrated that there is a significant correlation between VLA4 (P=< 0.0001) and 5 (P = 0.005) levels and HPSCs engraftment time. As the higher levels of VLA4 and 5, the shorter time HPSCs engraftment occurs. In contrast, there was no significant correlation between VLA6 (P = 0.2) and PSGL1 (P = 0.3) genes levels and engraftment time. So that, the patients with a good prognosis had a higher level of VLA4 and VLA5, but no relation was found between VLA6 and PSGL1. It is concluded that VLA4 and VLA5 expression could be considered a significant prognostic factor for HPSC transplantation.
... On the other hand, defective crosstalk between stem cell and endothelial cells has an important role in disease progression. In the hematopoietic system, miscommunication between HSCs and their vascular niche can lead to more severe conditions like skewed lineage production in hematopoiesis and anemia (Perlin et al, 2017). ...
Stem cells are the essential source of building blocks for tissue homeostasis and regeneration. Their behavior is dictated by both cell-intrinsic cues and extrinsic cues from the microenvironment, known as the stem cell niche. Interestingly, recent work began to demonstrate that hair follicle stem cells (HFSCs) are not only passive recipients of signals from the surroundings, but also actively send out signals to modulate the organization and function of their own niches. Here, we discuss recent findings, and briefly refer to the old, on the interaction of HFSCs and their niches with the emphasis on the outwards signals from HFSCs toward their niches. We also highlight recent technology advancements that further promote our understanding of HFSC niches. Taken together, the HFSCs emerge as a skin-organizing center rich in signaling output for niche remodeling during various stages of adult skin homeostasis. The intricate crosstalk between HFSCs and their niches adds important insight to skin biology that will inform clinical and bioengineering fields aiming to build complete and functional 3D organotypic cultures for skin replacement therapies.
... 7 As the shear stress in sinusoidal vessels is significantly lower than in arterioles, BM sinusoids are a preferential site for HSPC homing. 8 The adhesive interactions of HSPC with the BM endothelium share major similarities with the leukocyte adhesion cascade, which mediates leukocyte recruitment in inflammation. 9 Figure 1 Hematopoietic stem and progenitor cells bone marror homing in the context of hematopoietic stem cell transplantation. ...
... 7 As the shear stress in sinusoidal vessels is significantly lower than in arterioles, BM sinusoids are a preferential site for HSPC homing. 8 The adhesive interactions of HSPC with the BM endothelium share major similarities with the leukocyte adhesion cascade, which mediates leukocyte recruitment in inflammation. 9 Specifically, the rolling of HSPC and their subsequent firm adhesion onto the vascular endothelial cells of the BM are mediated by endothelium-expressed selectins and vascular cell adhesion molecule-1 (VCAM-1), respectively. ...
... Strikingly, when HSPCs migrate into the CHT through circulation and infiltrate across the vessel lumen to colonize the perivascular niche, a group of ECs remodel to form a surrounding pocket. This remodeling of the ECs, termed "EC cuddling, " is initiated by the arrival of HSPCs and promotes contact of HSPCs with other surrounding supporting cells such as stromal cells and fibroblasts (Perlin et al., 2017b) (Figure 2). Subsequently, the mesenchymal stromal cells anchor HSPCs, promoting HSPC division and expansion in the CHT niche. ...
During embryonic development, sequential waves of hematopoiesis give rise to blood-forming cells with diverse lineage potentials and self-renewal properties. This process must accomplish two important yet divergent goals: the rapid generation of differentiated blood cells to meet the needs of the developing embryo and the production of a reservoir of hematopoietic stem cells to provide for life-long hematopoiesis in the adult. Vascular beds in distinct anatomical sites of extraembryonic tissues and the embryo proper provide the necessary conditions to support these divergent objectives, suggesting a critical role for specialized vascular niche cells in regulating disparate blood cell fates during development. In this review, we will examine the current understanding of how organ- and stage-specific vascular niche specialization contributes to the development of the hematopoietic system.
... 20,21 It is well-established that bone marrow vasculature functions not only as the circulation conduit, but also actively contributes to niche signaling to regulate HSC self-renewal, differentiation, and regeneration. 22 Sublethal myeloablative irradiation depletes vascular and perivascular cells in the bone marrow via p53 pathway activation. 23 In turn, the stress on bone marrow endothelial cells causes HSC depletion and egress from the bone marrow to the periphery. ...
Hematopoietic stem cell transplantation (HSCT) is a treatment for many malignant, congenital, and acquired hematologic diseases. Some outstanding challenges in the HSCT field include the paucity of immunologically-matched donors, our inability to effectively expand hematopoeitic stem cells (HSCs) ex vivo, and the high infection risk during engraftment. Scientists are striving to develop protocols to generate, expand, and maintain HSCs ex vivo, however these are not yet ready for clinical application. Given these problems, advancing our understanding of HSC specification, regulation, and differentiation in preclinical models is essential to improve the therapeutic utility of HSCT. In this review, we link biomedical researchers and transplantation clinicians by discussing the potential therapeutic implications of recent fundamental HSC research in model organisms. We consider deficiencies in current HSCT practice, such as problems achieving adequate cell dose for successful and rapid engraftment, immense inflammatory cascade activation after myeloablation, and graft-vs-host disease. Furthermore, we discuss recent advances in the field of HSC biology and transplantation made in preclinical models of zebrafish, mouse, and nonhuman primates that could inform emerging practice for clinical application.
