Dataset Information

Reconstructed Single-Cell Fate Trajectories Define Lineage Plasticity Windows during Differentiation of Human PSC-Derived Distal Lung Progenitors.

ABSTRACT: Alveolar epithelial type 2 cells (AEC2s) are the facultative progenitors responsible for maintaining lung alveoli throughout life but are difficult to isolate from patients. Here, we engineer AEC2s from human pluripotent stem cells (PSCs) in vitro and use time-series single-cell RNA sequencing with lentiviral barcoding to profile the kinetics of their differentiation in comparison to primary fetal and adult AEC2 benchmarks. We observe bifurcating cell-fate trajectories as primordial lung progenitors differentiate in vitro, with some progeny reaching their AEC2 fate target, while others diverge to alternative non-lung endodermal fates. We develop a Continuous State Hidden Markov model to identify the timing and type of signals, such as overexuberant Wnt responses, that induce some early multipotent NKX2-1⁺ progenitors to lose lung fate. Finally, we find that this initial developmental plasticity is regulatable and subsides over time, ultimately resulting in PSC-derived AEC2s that exhibit a stable phenotype and nearly limitless self-renewal capacity.

SUBMITTER: Hurley K

PROVIDER: S-EPMC7469703 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

Reconstructed Single-Cell Fate Trajectories Define Lineage Plasticity Windows during Differentiation of Human PSC-Derived Distal Lung Progenitors.

Hurley Killian K Ding Jun J Villacorta-Martin Carlos C Herriges Michael J MJ Jacob Anjali A Vedaie Marall M Alysandratos Konstantinos D KD Sun Yuliang L YL Lin Chieh C Werder Rhiannon B RB Huang Jessie J Wilson Andrew A AA Mithal Aditya A Mostoslavsky Gustavo G Oglesby Irene I Caballero Ignacio S IS Guttentag Susan H SH Ahangari Farida F Kaminski Naftali N Rodriguez-Fraticelli Alejo A Camargo Fernando F Bar-Joseph Ziv Z Kotton Darrell N DN

Cell stem cell 20200130 4

Alveolar epithelial type 2 cells (AEC2s) are the facultative progenitors responsible for maintaining lung alveoli throughout life but are difficult to isolate from patients. Here, we engineer AEC2s from human pluripotent stem cells (PSCs) in vitro and use time-series single-cell RNA sequencing with lentiviral barcoding to profile the kinetics of their differentiation in comparison to primary fetal and adult AEC2 benchmarks. We observe bifurcating cell-fate trajectories as primordial lung progeni ...[more]

PMID: 32004478

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Project description:BackgroundRecently, the osteogenic potential of Adiponectin-labeled adipogenic lineage progenitors (Adipoq-lineage progenitors) in bone marrow has been observed to support bone maintenance and repair. However, little is known about the function of Schnurri-3 (SHN3, also known as HIVEP3) in other mesenchymal lineage cells, apart from its negative regulation of bone formation on osteoblasts.MethodIn this study, we used single-cell RNA sequencing (scRNA-seq) profiling to demonstrate that Adipoq-lineage progenitors express higher levels of Shn3 compared to other mesenchymal cell populations in mice and humans. To investigate the role of SHN3 in Adipoq-lineage progenitors, we generated a murine model specifically harboring a Shn3-deficient allele in Adipoq-expressing cells. Information of mice body weight was collected weekly to generate body weight curve. Bone phenotype was analyzed using micro-CT and histomorphometric studies. To eliminate the role of peripheral adipose tissue on bone, we collected adipose wet weight, performed intraperitoneal glucose tolerance tests and intraperitoneal insulin tolerance tests, and conducted a fat-transplantation study. Osteoblast and osteoclast functions were assessed through toluidine blue staining and TRAP staining, respectively. We further investigated the effect of Shn3 depletion on the differentiation of Adipoq-lineage progenitors through immunostaining and in vitro differentiation assays. Finally, we evaluated whether Shn3 deficiency in Adipoq-lineage progenitors affects the fracture healing process by generating bi-cortical femoral fracture models.ResultsDepletion of Shn3 in Adipoq-lineage progenitors resulted in a significant increase in trabecular bone mass and bone formation in vivo, without disrupting whole-body energy metabolism and skeletal development. Consistent with these findings, both cell-lineage tracing and functional assays revealed that Shn3 ablation effectively shifted the cell fate of Adipoq-lineage progenitors towards an osteogenic phenotype in the bone marrow. Furthermore, in vivo studies demonstrated that the lack of Shn3 in Adipoq-lineage progenitors also enhanced bone fracture healing under pathological conditions.ConclusionOverall, our findings provide a novel strategy for targeting the osteoanabolic potential of bone marrow Adipoq-lineage progenitors as a potential treatment for bone loss-related disorders.Translational potential of this articleWe have identified a novel gene target that directs the cell fate of a previously identified non-osteogenic cell population under physiological conditions. This study not only expands the therapeutic value of Shn3 ablation in treating osteoporotic or traumatic bone diseases but also provides new insights into the contribution of bone marrow Adipoq-lineage progenitors to osteogenesis. Thus, this article further supports Shn3 silencing as a valuable approach to treat osteopenia and accelerate fracture healing (see graphical abstract).

Dataset Information

Reconstructed Single-Cell Fate Trajectories Define Lineage Plasticity Windows during Differentiation of Human PSC-Derived Distal Lung Progenitors.

Publications

Reconstructed Single-Cell Fate Trajectories Define Lineage Plasticity Windows during Differentiation of Human PSC-Derived Distal Lung Progenitors.

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