biological properties of hsc scientific basis for hsct

Hematopoiesis—from the Greek term for "blood making"—is the adaptive process by which mature and functional blood cells are continuously replaced over the entire lifetime of an individual. Erythrocytes, platelets, and the various subsets of leukocytes all have finite although different life spans. As a consequence, the daily production of red blood cells, platelets, and neutrophils in homeostatic conditions amount to more than 300 billion cells

Metabolic gatekeeper function of B-lymphoid transcription factors

B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation

Generation of Hematopoietic Stem and Progenitor Cells from Human Pluripotent Stem Cells.

Human pluripotent stem cells (PSCs) have the potential to provide a virtually unlimited supply of cells for transplantation therapy. When combined with recent advances in genome editing technologies, human PSCs could offer various approaches that enable gene therapy, drug discovery, disease modeling, and in vitro modeling of human development. De novo generation of hematopoietic stem cells (HSCs) from human PSCs is an important focus in the field, since it enables autologous HSC transplantation to treat many blood disorders and malignancies. Although culture conditions have been established to generate a broad spectrum of hematopoietic progenitors from human PSCs, it remains a significant challenge to generate bona fide HSCs that possess sustained self-renewal and multilineage differentiation capacities upon transplantation. In this review, recent promising advances in the efforts to generate HSCs and hematopoietic progenitors from human PSCs in vitro and in vivo or from somatic cells are discussed