New paradigms on hematopoietic stem cell differentiation

Abstract

Ever since hematopoietic stem cells (HSCs) were first identified half a century ago, their differentiation roadmap has been extensively studied. The classical model of hematopoiesis has long held as a dogma that HSCs reside at the top of a hierarchy in which HSCs possess self-renewal capacity and can progressively give rise to all blood lineage cells. However, over the past several years, with advances in single cell technologies, this developmental scheme has been challenged. In this review, we discuss the evidence supporting heterogeneity within HSC and progenitor populations as well as the hierarchical models revised by novel approaches mainly in mouse system. These evolving views provide further understanding of hematopoiesis and highlight the complexity of hematopoietic differentiation.

Keywords: differentiation; hematopoietic stem cell; heterogeneity; hierarchy.

Figure 1. The classical hematopoietic hierarchy.

In the classical model, LT-HSCs sit at the top of hierarchy. LT-HSCs differentiate into ST-HSCs, and subsequently to MPPs with reduced self-renewal ability. Downstream of MPPs, a strict separation between the myeloid (CMPs) and lymphoid (CLPs) branches is the first step in lineage commitment. CMPs can generate MEPs and GMPs. CLPs give rise to lymphocytes and dendritic cells. MEPs differentiate into megakaryocytes/platelets and erythrocytes. GMPs produce granulocytes, macrophages, and dendritic cells. Hematopoietic differentiation is controlled by extrinsic cytokines and intrinsic transcription factors

Figure 2. The revised models for hematopoietic stem cell differentiation.

(A) My-Bi and Ly-Bi HSCs model. Ly-Bi HSCs reconstitute the myeloid lineage to a lesser extent than the lymphoid lineage, and vice versa. (B) Eaves’ lab defined α, β, γ, and δ cells according to the percentage of myeloid chimerism relative to that of lymphoid chimerism (M/L ratio). Single donor cell is defined as α cells when the M/L ratio exceeds 2, β cells when M/L ratio exceeds 0.25 but is less than 2, and γ/δ cells when it is less than 0.25. Therefore, α cells are myeloid-biased, β cells are balanced, and γ/δ cells are lymphoid-biased without 2nd transplantation capability. (C) vWF⁺ platelet-biased HSCs sit at the apex of the hierarchy, and can differentiate into all progenitors and mature cells. vWF⁻ lymphoid-biased HSCs reside downstream of vWF⁺ HSCs. LMPPs cannot give rise to the megakaryocyte/erythrocyte lineage. MEPs are directly derived from HSCs. (D) In the myeloid bypass model, the LT-HSC population contains CMRPs, MERPs, and MkRPs. These MyRPs are directly produced by HSCs. (E) MPP subtypes are separated into MPP1–4. MPP1 can give rise to all lineages. MPP2/3 are myeloid-biased and MPP4 is lymphoid-biased. In addition, MPP2 is platelet-biased. (F) In this model, MPPs differentiate into pre MegE, Pre GM and CLP. Pre MegE is upstream of MkP and pre CFU-E. Pre GM gives rise to GMP, and subsequently generates newly defined neutrophil precursors (Pre Neu)

Figure 3. Discrete vs. continuous hematopoietic differentiation model.

(A) The discrete differentiation model shows that HSCs differentiate to mature lineage the progression cells is a stepwise process following a tree-like hierarchy of oligo-, bi- and unipotent progenitors. (B) The continuous differentiation model shows that there is no obvious boundary in the hierarchy. Individual HSCs gradually acquire lineage biases along multiple directions without passing through discrete hierarchically organized progenitor populations

Figure 4. A reconciled model for hematopoietic stem cell differentiation.

In this model, HSCs first differentiate into MPP1/ST-HSC, then give rise to MPP2, MPP3 and MPP4 (LMPP). MPP2 can generate pre MegE, and subsequently, pre MegE gives rise to platelets through MkP or produce erythrocytes through Pre CFU-E. MPP3 mostly give rise to granulocyte and monocyte lineages, and MPP4 (LMPP) mainly contribute to lymphocytes