In vivo dynamics of human hematopoietic stem cells: novel concepts and future directions

Abstract

Unveiling the mechanisms and the cellular dynamics at the basis of human hematopoietic homeostasis has been a main focus for the scientific community since the discovery of a pool of multipotent hematopoietic stem cells (HSCs) capable of sustaining the hematopoietic output throughout life and after transplantation. Recently, new works shed light on the (1) differentiation paths, (2) size and replication rate of human HSC population at steady state, and (3) role of the distinct subpopulations comprising the hematopoietic stem and progenitor cell reservoir after transplantation. These papers exploited cutting-edge technologies, including vector integration site clonal tracking, spontaneous mutations, and deep transcriptome profiling. Here we discuss the latest updates in human hematopoietic system biology and in vivo dynamics, highlighting novel concepts and common findings deriving from different approaches and the future directions of these studies. Taken together, this information contributed to partially resolving the complexity of the in vivo HSC behavior and has major implications for HSC transplantation and gene therapy as well as for the development of future therapies.

Figure 1.

Models of human hematopoietic hierarchy. Representation of classical and revised models for HSC differentiation toward mature lineages based on recent literature.^- We reported in black the name of hematopoietic populations, whereas in dark red, the differentiation-driving genes. HSCs and MPPs shared similar HOXB6/HOXA2/PRDM16 gene modules but different metabolic state. HSC characteristics are listed on top left (in red), whereas MPP state is associated with activation of mechanisms listed on top right (orange). In the HSC/MPP cloud, preexisting lineage-specific modules are present at low levels and reinforced along differentiation: NEF2/GATA2 module represents the first attraction point for the megakaryocytic/erythroid specification, whereas CBPE/STAT1/TCF4 is associated with lymphoid-myeloid primed progenitor (LMPP) specification. Interestingly, dendritic cell (DC) and multilymphoid progenitor (MLP) cell fates appear to be associated with STAT1 expression, but IRF8 and ID3/TCF4 modules drive their final specification, respectively. The link between MLP and DC is in line with previous publications. B, B cells, CMP, common myeloid progenitors; E, erythrocytes; ETP, early T-cell progenitors; GMP, granulocytes monocytes progenitors; M, Monocytes; MEP, megakaryocytes erythrocytes progenitors; MK, megakaryocytes; NK, natural killer cells; PMN, polymorphonucleated cells; PreB/NK, B-cell and NK cell progenitors; T, T cells.

Figure 2.

Human HSPC dynamics in vivo. Schematic representation of the role of primitive and committed HSPC subpopulations during physiological aging and after transplantation. HSC pool increases in size during childhood, reaching the final adult reservoir that allows maintenance of hematopoietic production during life. As results of continuous challenging from external stimuli (such as infections, environmental pollution, and radiations), the HSC pool progressively loses its clonal complexity. Although previous works described increased frequency of HSC pool in the elderly,^, a comprehensive assessment of the maintenance, increase, or decrease of HSC number during aging remains to be elucidated. After transplantation, hematopoietic output is sustained by different HSPC subsets over time. In the initial engraftment, myeloid production is sustained by short-living myeloid progenitors (CMP/GMP). Short-term HSC/MPPs activated in the early phases provided the first hematopoietic reconstitution. Around 1 to 2 years after transplant, the HSPC compartment stabilized and LT HSCs maintained steady-state hematopoiesis.