Aged hematopoietic stem cells entrap regulatory T cells to create a prosurvival microenvironment

Liao, Weinian; Liu, Chaonan; Yang, Ke; Chen, Jun; Wu, Yiding; Zhang, Shuzhen; Yu, Kuan; Wang, Lisha; Ran, Li; Chen, Mo; Chen, Fang; Xu, Yang; Wang, Song; Wang, Fengchao; Zhang, Qian; Zhao, Jinghong; Ye, Lilin; Du, Changhong; Wang, Junping

doi:10.1038/s41423-023-01072-3

Cited by 7 publications

(5 citation statements)

References 71 publications

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“…4G). This observation is consistent with that MHC-II high stem cells represent a deeper quiescent state and are more resistant to stress-induced proliferation than MHC-II low stem cells 20,21 . These ndings underscore the pivotal role of cellular senescence in tumorigenesis and suggest that mutationaccumulated stem cells in C0 gained a clonal advantage during aging by upregulating their surface expression of MHC class II molecules.…”

Section: Heterogeneity Of Transcriptional Programs In Stem-like Cellssupporting

confidence: 90%

Single-cell Landscape of Malignant Transition: Unraveling Cancer Cell-of-Origin and Heterogeneous Tissue Microenvironment

Luo,

Liu,

Wen

et al. 2024

Preprint

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Understanding disease progression and sophisticated tumor ecosystems is imperative for investigating tumorigenesis mechanisms and developing novel prevention strategies. Here, we dissected heterogeneous microenvironments during malignant transitions by leveraging data from 1396 samples spanning 13 major tissues. Within transitional stem-like subpopulations highly enriched in precancers and cancers, we identified 30 recurring cellular states strongly linked to malignancy, including hypoxia and epithelial senescence, revealing a high degree of plasticity in epithelial stem cells. By characterizing dynamics in stem-cell crosstalk with the microenvironment along the pseudotime axis, we found differential roles of ANXA1 at different stages of tumor development. In precancerous stages, reduced ANXA1 levels promoted monocyte differentiation toward M1 macrophages and inflammatory responses, whereas during malignant progression, upregulated ANXA1 fostered M2 macrophage polarization and cancer-associated fibroblast transformation by increasing TGF-β production. Our spatiotemporal analysis further provided insights into mechanisms responsible for immunosuppression and a potential target to control evolution of precancer and mitigate the risk for cancer development.

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Section: Heterogeneity Of Transcriptional Programs In Stem-like Cellssupporting

confidence: 90%

Single-cell Landscape of Malignant Transition: Unraveling Cancer Cell-of-Origin and Heterogeneous Tissue Microenvironment

Luo,

Liu,

Wen

et al. 2024

Preprint

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“…How MSC contact leads to cAMP increase and PKA activation in HSPCs remains to be elucidated. However, we observed that it is independent of gap junction-mediated communication implicated in cAMP exchange between contacting osteoblasts 75 and T regulatory cells 48,50 .…”

Section: Discussionmentioning

confidence: 68%

“…Previous studies have reported gap junction mediated transfer of cAMP between adjacent cells [48][49][50] . To test if OP9M2 MSCs transfer cAMP to HSPCs through gap junctions, we used Carbenoxolone -a gap junction inhibitor and GAP27 connexin mimetic peptide to inhibit gap junction activity.…”

Section: ) Mscs Activate Camp/creb Signaling Pathway To Protect Human...mentioning

confidence: 98%

Mesenchymal Stromal Cells regulate human Hematopoietic Stem Cell survival and regeneration via cAMP/PKA pathway

Muddineni,

Even,

Zipin-Roitman

et al. 2023

Preprint

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Ionizing radiation and chemotherapy suppress normal Hematopoietic Stem and Progenitor Cells (HSPCs) function and present an inherent risk of developing bone marrow failure and secondary leukemias. Mesenchymal Stromal Cells (MSCs) constitute an essential HSPC niche component by regulating HSPC quiescence, self-renewal, survival, and differentiation. Yet, the underlying pro-regenerative signaling pathways activated in HSPCs by MSCs remain poorly understood. Here, using co-culture system of bone marrow-derived MSCs and HSPCs we established that irradiated HSPCs co-cultured with MSCs underwent significantly less apoptosis and maintained theirin vivorepopulating ability. We reveal that MSCs mediate protection by preserving pro-survival MCL1 protein levels in human HSPCs. Moreover, using unbiased HSPC transcriptomic analysis complemented with ex vivo and in vivo validation studies we discovered that MSCs activate cAMP/PKA/CREB signaling pathway in HSPCs to prevent MCL1 decline and apoptosis onset upon irradiation. Pharmacological activation of cAMP signaling pathway in human HSPCs replicated MSC mediated protection of HSPC functionality. Collectively, our results highlight the role of cAMP/PKA/CREB signaling pathway in MSC-HSPC cross-talk and its critical role in the regulation of survival and self-renewal ability of human HSPCs. Furthermore, we also revealed pharmacological agents that can mitigate radiation-induced hematological sequelae.

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“…Colony assay was performed as we previously reported [ 10 ]. 1000 sorted Lineage – cells from HSC cultures were plated into methylcellulose medium (STEMCELL Technologies) according to the manufacturer’s protocols.…”

Section: Methodsmentioning

confidence: 99%

“…The niche plays essential roles in transmitting the signal of hematopoietic demand to HSCs and regulating HSC maintenance through intercellular signals in the form of cell-bound or secreted factors, or physical interaction [ 1 , 2 ]. Unfortunately, myelosuppressive injury such as IR will profoundly disrupt the HSC niche, depleting and reorganizing the cellular niche of HSCs [ 10 – 12 ]. Of note, within the niche MKs are particularly resistant to myelosuppressive injury and remain functional in rodents for 7∼10 days after injury [ 13 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

Megakaryocytic IGF1 coordinates activation and ferroptosis to safeguard hematopoietic stem cell regeneration after radiation injury

Liao,

Chen,

Zhang

et al. 2024

Cell Commun Signal

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Background Hematopoietic stem cell (HSC) regeneration underlies hematopoietic recovery from myelosuppression, which is a life-threatening side effect of cytotoxicity. HSC niche is profoundly disrupted after myelosuppressive injury, while if and how the niche is reshaped and regulates HSC regeneration are poorly understood. Methods A mouse model of radiation injury-induced myelosuppression was built by exposing mice to a sublethal dose of ionizing radiation. The dynamic changes in the number, distribution and functionality of HSCs and megakaryocytes were determined by flow cytometry, immunofluorescence, colony assay and bone marrow transplantation, in combination with transcriptomic analysis. The communication between HSCs and megakaryocytes was determined using a coculture system and adoptive transfer. The signaling mechanism was investigated both in vivo and in vitro, and was consolidated using megakaryocyte-specific knockout mice and transgenic mice. Results Megakaryocytes become a predominant component of HSC niche and localize closer to HSCs after radiation injury. Meanwhile, transient insulin-like growth factor 1 (IGF1) hypersecretion is predominantly provoked in megakaryocytes after radiation injury, whereas HSCs regenerate paralleling megakaryocytic IGF1 hypersecretion. Mechanistically, HSCs are particularly susceptible to megakaryocytic IGF1 hypersecretion, and mTOR downstream of IGF1 signaling not only promotes activation including proliferation and mitochondrial oxidative metabolism of HSCs, but also inhibits ferritinophagy to restrict HSC ferroptosis. Consequently, the delicate coordination between proliferation, mitochondrial oxidative metabolism and ferroptosis ensures functional HSC expansion after radiation injury. Importantly, punctual IGF1 administration simultaneously promotes HSC regeneration and hematopoietic recovery after radiation injury, representing a superior therapeutic approach for myelosuppression. Conclusions Our study identifies megakaryocytes as a last line of defense against myelosuppressive injury and megakaryocytic IGF1 as a novel niche signal safeguarding HSC regeneration.

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Aged hematopoietic stem cells entrap regulatory T cells to create a prosurvival microenvironment

Cited by 7 publications

References 71 publications

Single-cell Landscape of Malignant Transition: Unraveling Cancer Cell-of-Origin and Heterogeneous Tissue Microenvironment

Single-cell Landscape of Malignant Transition: Unraveling Cancer Cell-of-Origin and Heterogeneous Tissue Microenvironment

Mesenchymal Stromal Cells regulate human Hematopoietic Stem Cell survival and regeneration via cAMP/PKA pathway

Megakaryocytic IGF1 coordinates activation and ferroptosis to safeguard hematopoietic stem cell regeneration after radiation injury

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