Irreversible destruction of bronchi and alveoli can lead to multiple incurable lung diseases. Identifying lung stem/progenitor cells with regenerative capacity and utilizing them to reconstruct functional tissue is one of the biggest hopes to reverse the damage and cure such diseases. Here we showed that a rare population of SOX9+ basal cells (BCs) located at airway epithelium rugae can regenerate adult human lung. Human SOX9+ BCs can be readily isolated by bronchoscopic brushing and indefinitely expanded in feeder-free condition. Expanded human SOX9+ BCs can give rise to alveolar and bronchiolar epithelium after being transplanted into injured mouse lung, with air-blood exchange system reconstructed and recipient’s lung function improved. Manipulation of lung microenvironment with Pirfenidone to suppress TGF-β signaling could further boost the transplantation efficiency. Moreover, we conducted the first autologous SOX9+ BCs transplantation clinical trial in two bronchiectasis patients. Lung tissue repair and pulmonary function enhancement was observed in patients 3–12 months after cell transplantation. Altogether our current work indicated that functional adult human lung structure can be reconstituted by orthotopic transplantation of tissue-specific stem/progenitor cells, which could be translated into a mature regenerative therapeutic strategy in near future.Electronic supplementary materialThe online version of this article (10.1007/s13238-018-0506-y) contains supplementary material, which is available to authorized users.

AbsractNeoantigens are ideal targets for dendritic cell (DC) vaccines. So far, only a few neoantigen-based DC vaccines have been investigated in clinical trials. Here, we reported a case of a patient with metastatic gastric cancer who received personalized neoantigen-loaded monocyte-derived dendritic cell (Neo-MoDC) vaccines followed by combination therapy of the Neo-MoDC and immune checkpoint inhibitor (ICI). The patient developed T cell responses against neoantigens after receiving the Neo-MoDC vaccine alone. The following combination therapy triggered a stronger immune response and mediated complete regression of all tumors for over 25 months till October, 2021. Peripheral blood mononuclear cells recognized seven of the eight vaccine neoantigens. And the frequency of neoantigen-specific T cell clones increased obviously after vaccination. Overall, this report describing a complete tumor regression in a gastric cancer patient mediated by Neo-MoDC vaccine in combination with ICI, and suggesting a promising treatment for patients with metastatic gastric cancer.

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Background Human pluripotent stem cell-derived limbal stem cells (hPSC-derived LSCs) provide a promising cell source for corneal transplants and ocular surface reconstruction. Although recent efforts in the identification of LSC markers have increased our understanding of the biology of LSCs, much more remains to be characterized in the developmental origin, cell fate determination, and identity of human LSCs. The lack of knowledge hindered the establishment of efficient differentiation protocols for generating hPSC-derived LSCs and held back their clinical application. Results Here, we performed a time-course single-cell RNA-seq to investigate transcriptional heterogeneity and expression changes of LSCs derived from human embryonic stem cells (hESCs). Based on current protocol, expression heterogeneity of reported LSC markers were identified in subpopulations of differentiated cells. EMT has been shown to occur during differentiation process, which could possibly result in generation of untargeted cells. Pseudotime trajectory analysis revealed transcriptional changes and signatures of commitment of hESCs-derived LSCs and their progeny—the transit amplifying cells. Conclusion Single-cell RNA-seq revealed time-course expression changes and significant transcriptional heterogeneity during hESC-derived LSC differentiation in vitro. Our results demonstrated candidate developmental trajectory and several new candidate markers for LSCs, which could facilitate elucidating the identity and developmental origin of human LSCs in vivo.