Permissive roles of cytokines interleukin-7 and Flt3 ligand in mouse B-cell lineage commitment

Abstract

Hematopoietic cells are continuously generated throughout life from hematopoietic stem cells, thus making hematopoiesis a favorable system to study developmental cell lineage commitment. The main factors incorporating environmental signals to developing hematopoietic cells are cytokines, which regulate commitment of hematopoietic progenitors to the different blood lineages by acting either in an instructive or a permissive manner. Fms-like tyrosine kinase-3 (Flt3) ligand (FL) and Interleukin-7 (IL-7) are cytokines pivotal for B-cell development, as manifested by the severely compromised B-cell development in their absence. However, their precise role in regulating B-cell commitment has been the subject of debate. In the present study we assessed the rescue of B-cell commitment in mice lacking IL-7 but simultaneously overexpressing FL. Results obtained demonstrate that FL overexpression in IL-7–deficient mice rescues B-cell commitment, resulting in significant Ebf1 and Pax5 expression in Ly6D+CD135+CD127+CD19− precursors and subsequent generation of normal numbers of CD19+ B-cell progenitors, therefore indicating that IL-7 can be dispensable for commitment to the B-cell lineage. Further analysis of Ly6D+CD135+CD127+CD19− progenitors in IL-7– or FL-deficient mice overexpressing Bcl2, as well as in IL-7 transgenic mice suggests that both FL and IL-7 regulate B-cell commitment in a permissive manner: FL by inducing proliferation of Ly6D+CD135+CD127+CD19− progenitors and IL-7 by providing survival signals to these progenitors.

Single‐cell RNA sequencing reveals developmental heterogeneity among early lymphoid progenitors

“…SiglecH is a specific marker for plasmacytoid dendritic cells (pDC), which also express B220 (Blasius et al , ; Zhang et al , ). Previously, it was shown that SiglecH was also expressed by a fraction of CLP and pre‐pro‐B cells (Medina et al , ), two populations partially overlapping with EPLM (von Muenchow et al , ). Since pDC also express the general dendritic cell marker CD11c (Singh‐Jasuja et al , ), we chose this as a third surface marker.…”

The changing face of hematopoiesis: a spectrum of options is available to stem cells

“…One difficulty with compartmentalizing cells in this manner is a lack of knowledge about the functions of some of these surface molecules during developmental progression. For example, the cellular functions of CD34, CD48 and CD150, and of markers such as Ly6D and SiglecH that are used to subdivide HPC in the case of early progenitors with lymphoid and myeloid potential (EPLM), are not known …”

Constraints Shape Cell Function and Morphology by Canalizing the Developmental Path along the Waddington's Landscape

“…For instance, Fms‐like tyrosine kinase‐3 ligand and Interleukin‐7—cytokines deemed pivotal for B‐cell development, as manifested by the severely compromised B‐cell development in their absence—were finally shown to be dispensable. [ 61 ]…”

“…For instance, Fms-like tyrosine kinase-3 ligand and Interleukin-7-cytokines deemed pivotal for B-cell development, as manifested by the severely compromised B-cell development in their absence-were finally shown to be dispensable. [61] It is likely that the opposition in between the two hypothesis is far too simple a viewpoint of decision-making by the hematological tissue. [62] Putting emphasis on the role of the permissive factors (constraints and topological features of the landscape) is not to deny a function for specialized molecular actors (cytokines), which can reinforce cell fate commitment by amplifying signal-to-noise ratio once a specific trajectory has been selected.…”