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A bone marrow stromal secretome screen identifies semaphorin 3A as a regulator of stress hematopoiesis

ABSTRACT: Bone marrow mesenchymal stromal cells (MSCs) are a major source of secreted factors that control hematopoietic stem and progenitor cell (HSPC) function. We previously reported the generation of revitalized MSCs (rMSCs), which support functional HSCs in culture more effectively than control MSCs. In a secretomic screen using rMSCs, we identified semaphorin 3A (SEM3A) as a secreted factor upregulated as part of a pro-inflammatory signature that may underly HSPC expansion by rMSCs. Similarly, SEM3A expression is upregulated by BM-MSCs in vivo in response to hematopoietic stress. Recombinant SEM3A directly promotes HSPC quiescence ex vivo. Analysis of a SEM3A loss of function mutation in vivo revealed hematopoietic progenitor expansion and accelerated recovery after myeloablation, consistent with a role for SEM3A in regulating the HSPC stress response. This work highlights proteomic screening using rMSCs as a method to identify novel secreted niche factors and uncovers a novel role for SEM3A in promoting HSPC quiescence in stress hematopoiesis.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Bone Marrow

SUBMITTER: Simone Sidoli

LAB HEAD: Simone Sidoli

PROVIDER: PXD065232 | Pride | 2025-07-11

REPOSITORIES: Pride

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			Action	DRS
	20220523_Stephanie_Daniel_1A.msf	Msf
	20220523_Stephanie_Daniel_1A.raw	Raw
	20220523_Stephanie_Daniel_1B.raw	Raw
	20220523_Stephanie_Daniel_2A.raw	Raw
	20220523_Stephanie_Daniel_2B.raw	Raw

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Project description:Osteolineage cell-derived extracellular vesicles (EVs) play a regulatory role in hematopoiesis and have been shown to promote the ex vivo expansion of human hematopoietic stem and progenitor cells (HSPCs). Here, we demonstrate that EVs from different human osteolineage sources do not have the same HSPC expansion promoting potential. Comparison of stimulatory and non-stimulatory osteolineage EVs by next-generation sequencing and mass spectrometry analyses revealed distinct microRNA and protein signatures identifying EV-derived candidate regulators of ex vivo HSPC expansion. Accordingly, the treatment of umbilical cord blood-derived CD34+ HSPCs with stimulatory EVs altered HSPC transcriptome, including genes with known roles in cell proliferation. An integrative bioinformatics approach, which connects the HSPC gene expression data with the candidate cargo in stimulatory EVs, delineated the potentially targeted biological functions and pathways during hematopoietic cell expansion and development. In conclusion, our study gives novel insights into the complex biological role of EVs in osteolineage cell-HSPC crosstalk and promotes the utility of EVs and their cargo as therapeutic agents in regenerative medicine.

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Project description:Transfer RNA (tRNA)-derived fragments (tRF) are emerging small noncoding (nc) RNAs that, while commonly altered in cancer, have poorly defined roles in tumorigenesis. Here we show that pseudouridylation (Ψ) of a stem-cell-enriched tRF subtype, mTOG, selectively inhibits malignant protein synthesis programs, thereby promoting engraftment and differentiation of myelodysplastic syndrome (MDS) hematopoietic stem and progenitor cells (HSPC). Building on evidence that mTOG-Ψ target the polyadenylate-binding protein cytoplasmic 1 (PABPC1), we employed HDX-MS to reveal critical interactions between mTOG and functional RNA-recognition motif (RRM) domains in PABPC1. Mechanistically, this hinders the recruitment of the translational co-activator PABPC1-interacting protein 1 (PAIP1) and strongly represses translation of transcripts sharing 5’UTR pyrimidine-enriched sequences (PES), including 5’ terminal oligopyrimidine tracts (TOP) that encode protein machinery components, and are frequently altered in cancer. Significantly, mTOG dysregulation leads to aberrantly increased 5’PES mRNA translation in malignant MDS-HSPC and is clinically associated with leukemic transformation and reduced patient survival. Taken together, these results define a critical role for tRF and Ψ in difficult-to-treat subsets of MDS characterized by high risk of progression to acute myeloid leukemia.

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