Abstract
Hematopoietic stem cells (HSCs), characterized by long-term self-renewal ability and multilineage differentiation potential, are a rare population of primitive progenitors that reside at the apex of hematopoietic hierarchy. HSC homeostasis is regulated not only by local conditions in the bone marrow (BM) microenvironment, but also by signals originating from distal organs. Among these organs, the lung has emerged as a pivotal extramedullary regulator of HSC homeostasis, with evidence implicating that both environmental insults (such as PM2.5, cigarette smoke, and chrysotile asbestos) and pulmonary pathologies (such as pulmonary fibrosis, lung adenocarcinoma, and infections) may lead to hematologic abnormalities. However, the mechanisms underlying the lung's regulatory roles in HSC function remain largely unknown.
Similar as gut, lung is another important habitat for commensal bacteria. Although the biomass of the lung microbiota is lower than gut microbiota, it also exerts significant influence on the host's immune function, susceptibility to diseases, and therapy responses Given that pulmonary microbial dysbiosis emerges as a hallmark of lung diseases and critically modulates systemic immune regulation, we hypothesized that lung microbial communities may also serve as a pivotal communicator bridging pulmonary pathophysiology and bone marrow HSC homeostasis.
In this study, utilizing PM2.5-induced lung injury and bleomycin-induced pulmonary fibrosis models, we identified pulmonary microbial dysbiosis as a critical pathogenic conduit leading to bone marrow HSC dysfunction. We observed that therapeutic restoration of microbial homeostasis via intratracheal administration or microbiota transplantation attenuated neutrophilic infiltration in lungs, reduced systemic inflammatory levels, and rescued self-renewal capacity and long-term reconstitution potential of HSCs in BM. We conducted single-cell RNA sequencing, microbiome sequencing, and widely targeted metabolomic analysis to elucidate the mechanisms by which lung microbiota affected HSCs. Taxonomic analysis pinpointed Prevotella melaninogenica as a key microbial contributor for HSC dysfunction. Combined single-cell sequencing and gene editing revealed IL-6 signaling pathway as the principal mechanism underlying hematopoietic impairment.
Collectively, our findings delineate a novel “lung microbiota-bone marrow axis” through which distal pulmonary microbial ecosystems govern HSC fate determination, and establish lung microbiota modulation as a promising therapeutic strategy for mitigating pollution- or fibrosis-associated hematological disorders. Given that lung inflammation and microbial dysbiosis are commonly observed in many hematological diseases, our study provides potential therapeutic approaches for improving HSC function and treating hematological diseases.
