Contrasting Responses of Lymphoid Progenitors to Canonical and Noncanonical Wnt Signals

Malhotra, Sachin; Baba, Yoshifumi; Garrett, Karla P.; Staal, Frank J. T.; Gerstein, Rachel M.; Kincade, Paul W.

doi:10.4049/jimmunol.181.6.3955

Cited by 73 publications

(79 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…49 It is unclear if normal HSCs ever exhibit such behavior, but lymphoid progenitors can reverse differentiation in response to Wnt signaling and be re-directed to an erythroid fate. 50 If it occurs, HSC oscillation might be reflected in CD86 expression.…”

Section: Discussionmentioning

confidence: 99%

CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential

Shimazu

Iida

Zhang

et al. 2012

Blood

Self Cite

View full text Add to dashboard Cite

IntroductionA large body of information exists about molecular mechanisms involved in maintaining HSC integrity, and many studies have identified unique markers associated with differentiation. 1 However, several of these parameters differ between strains of mice or change dramatically according to developmental age, activation status, or inflammation. [2][3][4] This issue gained importance with the realization that HSCs are normally heterogeneous and that functionally distinct subsets can be resolved according to phenotypes. [5][6][7][8] As one example, we discovered that a unique population of lineage marker Ϫ Sca-1 ϩ c-Kit ϩ (LSK) CD150 ϩ CD48 Ϫ HSCs lacked CD86. 9 CD86 Ϫ HSCs accumulated in old mice as well as young mice repeatedly injected with lipopolysaccharide (LPS). At least some HSCs in those animals had low ability to self-renew and restore the adaptive immune system when transplanted. In addition, HSCs in the chronically stimulated animals were abnormally in cycle. 9 However, the relation between those phenomena and CD86 loss was unclear.B7-1 (CD80) and B7-2 (CD86) are type I transmembrane proteins that were originally identified as ligands for CD28/CTLA-4. 10 Murine CD80 and CD86 share ϳ 28% amino acid identity, but both are capable of using conserved binding sites to recognize either human or mouse CD28. Although this is important for T-cell activation, another ligand, CTLA-4 functions as an inhibitory receptor for immune responses. 11 CD86 is constitutively expressed on dendritic cells, B cells, and thymic epithelial cells. CD80 is only expressed by activated B and T cells. Several reports suggest that CD80 and CD86 have overlapping functions because double knockout (KO) mice have more severe defects in immune responses than single KOs. 12 However, one report suggests there are differential functions. 13 Given the importance of CD80/86 for T-cell activation, blocking Abs are valuable in establishing tolerance during BM transplantation. 14 Marrow stromal cells express the CD28 ligand in close proximity to B-lineage progenitors, and CD28 might slightly enhance B lymphopoiesis. 15 CD86 is expressed by many HSCs, 7,9 but gain or loss relative to hematopoiesis has not been explored. We now report that CD86 loss on stem and progenitor cells closely parallels their loss of lymphopoietic potential. It is a uniquely useful marker for appreciating functional heterogeneity among HSCs that are otherwise similar. MethodsMice C57BL/6 (CD45.2 alloantigen), CD86-deficient (CD86 Ϫ/Ϫ ), and B6-SJL/ Ly5.1 (CD45.1 alloantigen) mice were purchased from The Jackson Laboratory. C57BL/6 ϫ SJL/Ly5.1 F 1 (CD45.1 and CD45.2 alloantigens) and RAG1/GFP (recombinase activator gene 1/green fluorescent protein) knock-in mice were bred and maintained in the Laboratory Animal Resource Center at the Oklahoma Medical Research Foundation. PU.1 fl/fl and C/EBP␣ fl/fl mice were bred with Mx1 Cre mice to generate PU.1 fl/fl or C/EBP␣ fl/fl ϪMx1 Cre mice. Those and C/EBP␤KO mice were bred and maintained in Beth Israel Deaconess Medical C...

show abstract

Section: Discussionmentioning

confidence: 99%

CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential

Shimazu

Iida

Zhang

et al. 2012

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast, depletion of β-catenin in hematopoietic progenitor cells or mature B cells has no overt impact on B-cell development [16,17,28]. Moreover, overexpression of Wnt5a in OP9 stromal cells promotes B-cell differentiation whereas overexpression of Wnt3a inhibits it [29][30][31]. These discrepancies highlight the need of novel genetic approaches in studying the effect of Wnt signaling in osteoblastsregulated B-cell development.…”

Section: Introductionmentioning

confidence: 99%

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

et al. 2015

View full text Add to dashboard Cite

Osteoblasts and perivascular stromal cells constitute essential niches for HSC selfrenewal and maintenance in the bone marrow. Wnt signaling is important to maintain HSC integrity. However, the paracrine role of Wnt proteins in osteoblasts-supported HSC maintenance and differentiation remains unclear. Here, we investigated hematopoiesis in mice with Wntless (Wls) deficiency in osteoblasts or Nestin-positive mesenchymal progenitor cells, which presumptively block Wnt secretion in osteoblasts. We detected defective B-cell lymphopoiesis and abnormal T-cell infiltration in the bone marrow of Wls mutant mice. Notably, no impact on HSC frequency and repopulation in the bone marrow was observed with the loss of osteoblastic Wls. Our findings revealed a supportive role of Wnts in osteoblasts-regulated B-cell lymphopoiesis. They also suggest a preferential niche role of osteoblastic Wnts for lymphoid cells rather than HSCs, providing new clues for the molecular nature of distinct niches occupied by different hematopoietic cells.Keywords: B cell r HSC maintenance r Osteoblast r T-cell infiltration r Wntless Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHSCs that periodically generate all hematopoietic lineages are mostly stored in vascular or endosteal niches in the bone marrow [1]. Vascular niches consist of sinusoidal endothelium cells [2][3][4] whereas endosteal niches are mainly composed of osteoblasts [5,6]. These niche cells are important to regulate HSCs self-renewal and maintenance. Recent evidence also reveals that perivascular Nestin + mesenchymal progenitor cells form a supportive niche for HSCs [3,7,8]. In addition, studies from Dr. Morrison suggest that HSCs mainly reside in the perivascular niches whereas the early lymphoid progenitor cells prefer to locate at endosteal niches [9,10].Correspondence: Dr. Xizhi Guo e-mail: xzguo2005@sjtu.edu.cn; zjyao@sjtu.edu.cnCompelling evidence reveals that Wnt signaling is an important regulator for HSCs integrity and function. Wnt proteins, which consist of 19 members in mammals, could be transduced through canonical or noncanonical signaling pathways [11]. β-Catenin is the key and obligatory mediator of canonical Wnt signaling. Stabilized β-catenin expression expands the pool of HSCs and leads to deficiency in HSCs repopulation capacity [12,13]. Conversely, deletion of β-catenin or Wnt3a leads to defective HSCs long-term maintenance [14,15]. Nevertheless, several lines of evidence also indicate that β-catenin is dispensable for HSCs maintenance [16,17]. On the other hand, inhibition of environmental canonical Wnt signaling in osteoblasts impairs HSCs self-renewal and quiescence [18]. Collectively, canonical Wnt signaling is revealed to * These authors contributed equally to this work. regulate HSCs self-renewal in a dosage-dependent manner [19]. In addition, noncanonical Wnt signaling is also reported to sustain HSCs maintenance and aging [20,21]. Osteoblasts also support B-cell commitment an...

show abstract

“…It was previously shown that hES cells can differentiate into hematopoietic lineages when co-cultured with OP9 stroma cells. Furthermore, OP9 ectopically expressing Wnt3A (OP9W3a), 24 activating the canonical Wnt pathway, augments hematopoiesis 25 ; whereas OP9 expressing Delta-like1 (OP9D) specifically supports T-lineage differentiation. 26 Therefore, as seen in culture, we hypothesized that co-injection of iPS cells with OP9 stroma cells could improve hematopoietic differentiation within the teratomas through physical interaction or secreted factors.…”

Section: Op9 Stroma Cells Increase Intra-teratoma Hematopoiesismentioning

confidence: 99%

In vivo generation of transplantable human hematopoietic cells from induced pluripotent stem cells

Amabile

Welner

Nombela‐Arrieta

et al. 2013

Blood

192

173

View full text Add to dashboard Cite

show abstract

Contrasting Responses of Lymphoid Progenitors to Canonical and Noncanonical Wnt Signals

Cited by 73 publications

References 61 publications

CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential

CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

In vivo generation of transplantable human hematopoietic cells from induced pluripotent stem cells

Contact Info

Product

Resources

About