Engraftment Outcome of CRISPR/Cas9-Edited Hematopoietic Stem Cells for Genetic Diseases: A Systematic Review and Meta-Analysis of Preclinical Evidence.

The role of chemokine activation of Rac GTPases in hematopoietic stem cell marrow homing, retention, and peripheral mobilization

MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia.

Mechanisms of hematopoietic stem cell mobilization: When innate immunity assails the cells that make blood and bone

Transcriptome Analysis Identifies Regulators of Hematopoietic Stem and Progenitor Cells

PAR1 Expression Predicts Clinical G-CSF CD34+ HSPC Mobilization and Repopulation Potential in Transplanted Patients.

Blood Cell Replenishment and Bone Marrow Stem Cell Pool Renewal Are Regulated By Different Circadian Peaks Via Norepinephrine and TNFα/S1P Signaling

Endothelial cells (ECs) line blood vessels and serve as a niche for hematopoietic stem and progenitor cells (HSPCs). Recent data point to tissue-specific EC specialization as well as heterogeneity; however, it remains unclear how ECs acquire these properties. Here, by combining live-imaging-based lineage-tracing and single-cell transcriptomics in zebrafish embryos, we identify an unexpected origin for part of the vascular HSPC niche. We find that islet1 (isl1)-expressing cells are the progenitors of the venous ECs that constitute the majority of the HSPC niche. These isl1-expressing cells surprisingly originate from the endoderm and differentiate into ECs in a process dependent on Bmp-Smad signaling and subsequently requiring npas4l (cloche) function. Single-cell RNA sequencing analyses show that isl1-derived ECs express a set of genes that reflect their distinct origin. This study demonstrates that endothelial specialization in the HSPC niche is determined at least in part by the origin of the ECs.

Mitochondria Transfer from Hematopoietic Stem and Progenitor Cells to Pdgfrα+/Sca-1-/CD48dim BM Stromal Cells Via CX43 Gap Junctions and AMPK Signaling Inversely Regulate ROS Generation in Both Cell Populations

Lipid nanoparticle-mediated epitope editing in human HSPCs enables resistance to CD45-directed CAR-T cell therapy

Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia.

Administration of Granulocyte Colony-Stimulating Factor Post-Transplant Impedes Engraftment of CRISPR-Cas9 Edited Long-Term Repopulating Hematopoietic Stem and Progenitor Cells

Hematopoietic stem cells (HSC) primarily reside in the bone marrow (BM) and possess the ability of self-renewal and differentiation to any progenitor or mature blood cell through hematopoiesis. Adult HSCs are found in specialized bone marrow niches that are essential for the regulation of quiescence, mobilization and differentiation of HSCs. Multiple studies have attempted to shed light on the complex signaling pathways between stromal and hematopoietic cells of the niche at steady state, inflammation and disease. Endothelial cells (EC) and perivascular stromal niches are known to illicit paracrine signals for the control of HSC maintenance and function. Curative transplantation approaches dwell on the effective activation and mobilization of hematopoietic stem and progenitor cells (HSPC) to the blood circulation. Current pharmaceutical approaches involve the use of mobilizing agent granulocyte-colony stimulating factor (G-CSF). The Angiopoietin/Tie (Ang/Tie) signaling pathway is essential for embryonic blood and lymphatic vessel development and maturation as well as vessel homeostasis in the adult. Few studies attempted to investigate Ang/Tie signaling in the BM stem cell niche. Angiopoietin-1 (Ang1) has been studied in the context of HSC maintenance and quiescence in the BM. It has also been shown that Ang1/Tie2 signaling is important for vascular recovery following BM irradiation. Besides the well-established role of Ang/Tie signaling in EC, Tie2 receptor is also known for its expression in HSPC. These findings led to the hypothesis that Ang/Tie signaling might impact HSPC in the bone marrow niche. The present study investigated Angiopoietin-2 (Ang2) in vivo in the context of HSPC activation, egress and mobilization to the periphery. For this purpose, both genetic approaches as well as pharmaceutical inhibition of Ang2 were employed. Although Ang2 did effect HSPC egress at steady state, Ang2KO mice demonstrated a delayed and reduced HSPC mobilization to the periphery upon G-CSF stimulation. Further dissection of the phenotype revealed that the absence of Ang2 hindered the prompt activation of HSPC rather than the process of mobilization. The bone marrow vasculature and its function seemed unaffected by Ang2 at steady state and upon G-CSF mobilization. Further assessment of Ang2 function on HSPC was carried out in the context of hematopoietic reconstitution upon lethal irradiation. The reduced capability of immune cell reconstitution in Ang2KO mice confirmed the ligand’s importance in replenishing the BM. The next focus of the thesis was elucidating the roles of Tie1 receptor on ECs in the BM in vivo. The investigation of HSPC egress and G-CSF-induced mobilization revealed fewer HSPCs in the periphery. Functional assays on blood vessels revealed that subtle changes in the vasculature are responsible for the reduced ability of HSPC mobilization in Tie1iECKO mice. Finally, since Tie1 receptor is not only expressed in ECs but also in HSPCs, this study involved the investigation of the receptor’s role in progenitor colony formation in vitro and BM reconstitution in vivo. Colony forming unit (CFU) assays revealed that Tie1 deletion on HSPC (Tie1KO) reduced the cells' ability to form differentiated colonies. Serial and competitive transplantations in mice confirmed the reduced ability of Tie1-deleted HSPC to repopulate the myeloid BM compartment of lethally irradiated mice. The present thesis sheds lights on the interactions of blood vessels and HSPCs from an Ang/Tie-centric perspective. The experiments have unraveled the contribution of the context-dependent partial agonist Ang2, and the orphan receptor Tie1 in HSPC egress, mobilization and bone marrow reconstitution. These new discoveries are important in elucidating Ang/Tie signaling in the BM and potentially contribute to HSPC mobilization research for the treatment of hematological malignancies.

Comparing the Impact of NHEJ-CRISPR/Cas9 and Base Gene Editing on Rhesus Macaque Hematopoietic Stem Cell Clonal Behavior and Integrity

Hematopoietic Stem Cells and Their BM Stromal Microenvironment Share a Dynamic Inverse Metabolic State During Quiescence and Proliferation Via ROS Transfer Between The Two Populations

Adenylate Kinase 2 Links Energy Metabolism and Cell Fate in Hematopoietic Stem and Progenitor Cells