Abstract
The origin and specification of human dendritic cells (DCs) have not been investigated at clonal level. Using clonal assays combined with statistical computation to quantify the yield of granulocytes, monocytes, lymphocytes and three subsets of DCs from single human CD34+ progenitor cells, we show DC lineage specification occurs in parallel with myeloid and lymphoid lineages in HSCs, starting as a lineage bias defined by specific transcriptional programs correlated with the relative IRF8/PU.1 ratios, which is transmitted to most progeny and reinforced by FLT3L-driven IRF8 upregulation over division. We propose a model in which DC lineage specification is driven by parallel and inheritable transcriptional programs in HSCs, and reinforced over cell division by recursive interaction between transcriptional programs and extrinsic signals.
Highlights
Single-cell transplantation[14] and endogenous bar-coding 15 has suggested that most mouse myeloid cells derive from HSCs that are restricted to the myeloid lineage, leading to the idea of ‘early imprinting or commitment’ at the HSC stage 10
Because megakaryocyte-erythroid progenitor (MEP) do not produce dendritic cells (DCs), lymphoid or myeloid cells 1819, we evaluated the developmental potential of the other nine progenitor populations into seven mature cell types: granulocytes (G), monocytes (M), lymphocytes (L), B cells (B) and natural killer (NK) cells, and three DC subsets—plasmacytoid DC (pDC), DC1, and DC2 using two in vitro systems: a colony formation assay for the G, M, megakaryocyte (Mk) and erythrocyte (Er) lineages (Supplementary Fig. 1a) and a culture containing MS5 and OP9 stromal cells, and FLT3L, SCF and GM-CSF cytokines (MP+FSG), to assess G, M, L, A, C and P lineages (Fig. 1b)
Various progenitor subsets were observed after a certain number of divisions: CD34+CD38-CD45RA+CD7- lymphoid-primed multipotent progenitor (LMPP) appeared at division 1–2, CD34+CD38+CD45RA-CD7- common myeloid progenitors (CMP) and CD34+CD38+CD45RA+CD7-CD123+CD115GMDPs at division 3, CD34+CD38-CD45RA+CD7+ B-NK cell progenitor (BNKP) and CD34+CD38+CD45RA+CD7-CD123+CD115+ monocyte-DC progenitor (MDP) at division 5, and CD34+CD38+CD45RA+CD7-CD123hiCD115- common DC progenitor (CDP) at division 7 (Fig. 1c), indicating a hierarchy among progenitor phenotypes
Summary
Single-cell transplantation[14] and endogenous bar-coding 15 has suggested that most mouse myeloid cells derive from HSCs that are restricted to the myeloid lineage, leading to the idea of ‘early imprinting or commitment’ at the HSC stage 10. Irf[8] expression and function(i.e. driving DC and monocyte development) are thought to occur after the lymphoid-primed multipotent progenitor (LMPP) stage 169, 17. The concentration and the relative dosage ratio of PU.[1] and IRF8 were highly correlated with specific lineage biases, while FLT3L drove and maintained the DC lineage program over cell division. These results indicate that combinatorial dosage of a common set of transcription factors in HSC-MPPs can shape parallel and inheritable programs for distinct hematopoietic lineages, which are reinforced through recursive interaction with environmental cytokines
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