Transient Expression of GATA3 in Hematopoietic Stem Cells Facilitates Helper Innate Lymphoid Cell Differentiation

Tufa, Dejene M.; Yingst, Ashley; Shank, Tyler; Shim, So Yeon; Trahan, G. Devon; Lake, Jessica; Woods, Renee; Jones, Kenneth L.; Verneris, Michael R.

doi:10.3389/fimmu.2019.00510

Cited by 9 publications

(9 citation statements)

References 45 publications

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“…While studying in vitro differentiation of CD56 + lymphocytes from CD34 + progenitors, we noticed a minor population of non-ILC lineage cells that differentiated early in the cultures and were CD11a low and negative for ILC markers including CD56, CD94, CD336, CD117 and CD294 16 . We sought to both characterize these cells and to determine whether they promoted or suppressed CD56 + lymphocyte development.…”

Section: Scf and Flt3l Drive The Differentiation Of Hscs Into Prlr + mentioning

confidence: 95%

“…4A-C). Moreover, the CD34 + PRLR + progenitors do not express integrin α4β7, a marker that defines innate lymphoid precursors with the potential to develop into ILCs 12,15,16,57 (Fig. 4C).…”

Section: Prlr-expressing Progenitors Are Derived From Gmps and Differmentioning

confidence: 99%

“…RNA purity and concentration were measured on a NanoDrop (Thermofisher Scientific). Preparation of libraries, sequencing, alignment of reads and derivation of expression (FPKM) were as described before 16 . R v3.…”

Section: Prl Treatment and Differentiation Of Cd34 + Hscs After 4 Damentioning

confidence: 99%

“…Taqman gene expression assays for PRL (Hs00168730_m1), PRLR (Hs01061477_m1), SMAD7 (Hs00998193_ m1) and TGF-β1 (Hs00998133_m1) were purchased from Thermofisher Scientific. The qPCR experiments were done as previously described 16 .…”

Section: Prl Treatment and Differentiation Of Cd34 + Hscs After 4 Damentioning

confidence: 99%

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

Tufa

Shank

Yingst

et al. 2020

Sci Rep

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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 colonystimulating 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. Hematopoietic differentiation is specified by a multitude of soluble and membrane-bound molecules produced both within and outside of the hematopoietic system that influence cell fate decisions 1-6. In line with this, numerous cytokines including interleukin (IL)-1, IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IL-23, IL-25 and IL-33 have been shown to modulate the development of NK cells and other innate lymphoid cells (ILCs) 7-14. Moreover, NK cells and other ILCs require different transcription factors such as Tbet, RORc and Gata3 for their development 7,15,16. Multi-lymphoid progenitor (MLP) differentiate into the common ILC progenitor and this cell then gives rise to NK cells and all helper ILCs (i.e., ILC1, 2 and 3) 12-14,17. NK cells and helper ILCs are distinguished by specific transcription factor expression, cytokine production and function 9,13,14,18,19. We have used in vitro differentiation to study these processes and over the last decade have found that both NK cells and helper ILCs (particularly, ILC1s and ILC3s) develop in this system and similarly express CD56 16,20-23. Therefore, throughout this manuscript we use the term CD56 + lymphocytes to describe all CD56 expressing cells. Prolactin (PRL) is a neuroendocrine hormone best known for its role in lactation. However, PRL also regulates hematopoietic cell development and homeostasis 24-28. Specifically, PRL enhances the development of myeloid and

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Section: Scf and Flt3l Drive The Differentiation Of Hscs Into Prlr + mentioning

confidence: 95%

Section: Prlr-expressing Progenitors Are Derived From Gmps and Differmentioning

confidence: 99%

Section: Prl Treatment and Differentiation Of Cd34 + Hscs After 4 Damentioning

confidence: 99%

Section: Prl Treatment and Differentiation Of Cd34 + Hscs After 4 Damentioning

confidence: 99%

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

Tufa

Shank

Yingst

et al. 2020

Sci Rep

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“…We investigated whether CILPs were present in UCB CD34 + and integrin 47 + compartments (1,26,27). Nearly all UCB-derived CD34 + cells were CD117 + , whereas only ~3% of these were 47 + (fig.…”

Section: Human Cilps Are Contained In Cd34 + 47 + Cd117 + Hscsmentioning

confidence: 99%

Human innate lymphoid cell precursors express CD48 that modulates ILC differentiation through 2B4 signaling

Tufa¹,

Yingst²,

Trahan³

et al. 2020

Sci. Immunol.

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Innate lymphoid cells (ILCs) develop from common lymphoid progenitors (CLPs), which further differentiate into the common ILC progenitor (CILP) that can give rise to both ILCs and natural killer (NK) cells. Murine ILC intermediates have recently been characterized, but the human counterparts and their developmental trajectories have not yet been identified, largely due to the lack of homologous surface receptors in both organisms. Here, we show that human CILPs (CD34+CD117+α4β7+Lin−) acquire CD48 and CD52, which define NK progenitors (NKPs) and ILC precursors (ILCPs). Two distinct NK cell subsets were generated in vitro from CD34+CD117+α4β7+Lin−CD48−CD52+ and CD34+CD117+α4β7+Lin−CD48+CD52+ NKPs, respectively. Independent of NKPs, ILCPs exist in the CD34+CD117+α4β7+Lin−CD48+CD52+ subset and give rise to ILC1s, ILC2s, and NCR+ ILC3s, whereas CD34+CD117+α4β7+Lin−CD48+CD52− ILCPs give rise to a distinct subset of ILC3s that have lymphoid tissue inducer (LTi)–like properties. In addition, CD48-expressing CD34+CD117+α4β7+Lin− precursors give rise to tissue-associated ILCs in vivo. We also observed that the interaction of 2B4 with CD48 induced differentiation of ILC2s, and together, these findings show that expression of CD48 by human ILCPs modulates ILC differentiation.

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Early Development of Innate Lymphoid Cells

et al. 2022

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Transient Expression of GATA3 in Hematopoietic Stem Cells Facilitates Helper Innate Lymphoid Cell Differentiation

Cited by 9 publications

References 45 publications

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

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

Human innate lymphoid cell precursors express CD48 that modulates ILC differentiation through 2B4 signaling

Early Development of Innate Lymphoid Cells

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