Prolactin Acts on Myeloid Progenitors to Modulate SMAD7 Expression and Enhance Hematopoietic Stem Cell Differentiation into the NK Cell Lineage

Sci Rep. 2020 Apr 14;10(1):6335. doi: 10.1038/s41598-020-63346-4.


Numerous cell types modulate hematopoiesis through soluble and membrane bound molecules. Whether developing hematopoietic progenitors of a particular lineage modulate the differentiation of other hematopoietic lineages is largely unknown. Here we aimed to investigate the influence of myeloid progenitors on CD34+ cell differentiation into CD56+ innate lymphocytes. Sorted CD34+ cells cultured in the presence of stem cell factor (SCF) and FMS-like tyrosine kinase 3 ligand (FLT3L) give rise to numerous cell types, including progenitors that expressed the prolactin receptor (PRLR). These CD34+PRLR+ myeloid-lineage progenitors were derived from granulocyte monocyte precursors (GMPs) and could develop into granulocytes in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Moreover, CD34+PRLR+ myeloid progenitors lacked lymphoid developmental potential, but when stimulated with prolactin (PRL) they increased the differentiation of other CD34+ cell populations into the NK lineage in a non-contact dependent manner. Both mRNA and protein analyses show that PRL increased mothers against decapentaplegic homolog 7 (SMAD7) in CD34+PRLR+ myeloid cells, which reduced the production of transforming growth factor beta 1 (TGF-β1), a cytokine known to inhibit CD56+ cell development. Thus, we uncover an axis whereby CD34+PRLR+ GMPs inhibit CD56+ lineage development through TGF-β1 production and PRL stimulation leads to SMAD7 activation, repression of TGF-β1, resulting in CD56+ cell development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, CD34 / genetics
  • Antigens, CD34 / immunology
  • CD56 Antigen / genetics
  • CD56 Antigen / immunology
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Gene Expression Regulation, Developmental / genetics
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / metabolism
  • Lymphocytes / cytology
  • Lymphocytes / immunology
  • Lymphopoiesis / genetics*
  • Myeloid Progenitor Cells / cytology
  • Myeloid Progenitor Cells / metabolism
  • Prolactin / genetics*
  • Receptors, Prolactin / genetics*
  • Smad7 Protein / genetics*
  • Transforming Growth Factor beta1 / genetics*
  • fms-Like Tyrosine Kinase 3 / genetics


  • Antigens, CD34
  • CD56 Antigen
  • Receptors, Prolactin
  • Smad7 Protein
  • Transforming Growth Factor beta1
  • Prolactin
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3