{"doi":"10.1101/2025.08.29.673055","title":"A systems approach to B-cell development identifies BDNF as a regulator of human B lymphopoiesis","abstract":"Abstract B-cell aplasia is a major consequence of aging, chemotherapy, and B-cell-depleting immunotherapies, compromising immune protection against infections, cancer, and vaccines. Yet, unlike the myeloid and erythroid lineages, no strategy exists to accelerate human B-cell reconstitution. Here, we used an integrative systems biology approach to identify regulators of human B lymphopoiesis in the bone marrow (BM) microenvironment. By combining single-cell transcriptomic analysis of human BM with intercellular communication mapping, we generated an initial set of candidate factors predicted to act on developing B cells. To distinguish biologically meaningful putative regulators from a broad candidate space, we further intersected these findings with orthogonal human datasets capturing age-impaired B lymphopoiesis and protein dynamics associated with B-cell depletion and reconstitution. This convergent prioritization strategy highlighted a focused set of putative regulators, among which brain-derived neurotrophic factor (BDNF) emerged repeatedly as a top putative regulator. Functional interrogation in progenitor BM cells showed that several prioritized putative regulators induced transcriptional programs linked to early immune development, with BDNF consistently promoting pathways associated with B-cell differentiation. Importantly, in a human in vitro BM co-culture system, BDNF enhanced the differentiation of CD34+ hematopoietic progenitors into CD19+ progenitor B cells. Together, these findings identify BDNF as a previously unrecognized regulator of early human B lymphopoiesis and establish a general framework for uncovering functional hematopoietic regulators by integrating single-cell analysis with complementary biological and clinical signals. This approach may support future strategies to improve immune reconstitution in settings of prolonged B-cell depletion.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":574123,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9607,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1481915,"name":"Yuval Klein","orcid":null,"position":1,"is_corresponding":false},{"id":4583,"name":"Ayelet Alpert","orcid":null,"position":2,"is_corresponding":false},{"id":1481916,"name":"Amir Grau","orcid":null,"position":3,"is_corresponding":false},{"id":502203,"name":"Doron Melamed","orcid":null,"position":4,"is_corresponding":false},{"id":1359417,"name":"Timothy J Few-Cooper","orcid":null,"position":5,"is_corresponding":false},{"id":4582,"name":"Neta Milman","orcid":null,"position":6,"is_corresponding":false},{"id":3339,"name":"Shai S. Shen-Orr","orcid":"0000-0002-6991-7736","position":7,"is_corresponding":false},{"id":1481914,"name":"Neta Nevo","orcid":null,"position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T02:57:40.686992Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}