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Todd W. Dowrey, Samuel F. Cranston, Nicholas Skvir, Yvonne Lok, Brian Gould, Bradley Petrowitz, Daniel Villar, Jidong Shan, Marianne James, Mark Dodge, Anna C. Belkina, Richard M. Giadone, Sofiya Milman, Paola Sebastiani, Thomas T. Perls, Stacy L. Anderson, George J. Murphy.
CReM Latest
- Publications
Individuals homozygous for the ‘‘Z’’ mutation in alpha-1 antitrypsin deficiency are known to be at increased
risk for liver disease. It has also become clear that some degree of risk is similarly conferred by the heterozygous
state. A lack ofmodel systems that recapitulate heterozygosity in human hepatocytes has limited the
ability to study the impact of a single Z alpha-1 antitrypsin (ZAAT) allele on hepatocyte biology. Here, we
describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the
effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps). We find that heterozygous MZ iHeps exhibit
an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and
downstream perturbations including altered endoplasmic reticulum (ER) and mitochondrial morphology,
reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in cell
subpopulations. Our model of MZ heterozygosity thus provides evidence that a single Z allele is sufficient
to disrupt hepatocyte homeostatic function.
- Publications
Dysfunction of alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of lung alveoli,
is implicated in pulmonary disease pathogenesis, highlighting the importance of human in vitro
models. However, AEC2-like cells in culture have yet to be directly compared to their in vivo
counterparts at single-cell resolution. Here, we performed head-to-head comparisons among the
transcriptomes of primary (1°) adult human AEC2s, their cultured progeny, and human induced
pluripotent stem cell–derived AEC2s (iAEC2s). We found each population occupied a distinct
transcriptomic space with cultured AEC2s (1° and iAEC2s) exhibiting similarities to and differences
from freshly purified 1° cells. Across each cell type, we found an inverse relationship between
proliferative and maturation states, with preculture 1° AEC2s being most quiescent/mature and
iAEC2s being most proliferative/least mature. Cultures of either type of human AEC2s did not
generate detectable alveolar type 1 cells in these defined conditions; however, a subset of iAEC2s
cocultured with fibroblasts acquired a transitional cell state described in mice and humans to arise
during fibrosis or following injury. Hence, we provide direct comparisons of the transcriptomic
programs of 1° and engineered AEC2s, 2 in vitro models that can be harnessed to study human lung
health and disease.
- Publications
Age-related changes in immune cell composition and functionality are associated with multimorbidity
and mortality. However, many centenarians delay the onset of aging-related disease suggesting the presence of elite
immunity that remains highly functional at extreme old age.
To identify immune-specific patterns of aging and extreme human longevity, we analyzed novel single cell
profiles from the peripheral blood mononuclear cells (PBMCs) of a random sample of 7 centenarians (mean age 106)
and publicly available single cell RNA-sequencing (scRNA-seq) datasets that included an additional 7 centenarians as
well as 52 people at younger ages (20–89 years).
The analysis confirmed known shifts in the ratio of lymphocytes to myeloid cells, and noncytotoxic to
cytotoxic cell distributions with aging, but also identified significant shifts from CD4+ T cell to B cell populations in
centenarians suggesting a history of exposure to natural and environmental immunogens. We validated several of
these findings using flow cytometry analysis of the same samples. Our transcriptional analysis identified cell type
signatures specific to exceptional longevity that included genes with age-related changes (e.g., increased expression of
STK17A, a gene known to be involved in DNA damage response) as well as genes expressed uniquely in centenarians’
PBMCs (e.g., S100A4, part of the S100 protein family studied in age-related disease and connected to longevity and
metabolic regulation).
Collectively, these data suggest that centenarians harbor unique, highly functional immune systems
that have successfully adapted to a history of insults allowing for the achievement of exceptional longevity.
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- Publications
A robust method of producing mature T cells from iPSCs is needed to realize their therapeutic potential. NOTCH1 is known to be required for the production of hematopoietic progenitor cells with T cell potential in vivo. Here we identify a critical window during mesodermal differentiation when Notch activation robustly improves access to definitive hematopoietic progenitors with T/NK cell lineage potential. Low-density progenitors on either OP9-hDLL4 feeder cells or hDLL4-coated plates favored T cell maturation into TCRab+CD3+CD8+ cells that express expected T cell markers, upregulate activation markers, and proliferate in response to T cell stimulus. Single-cell RNAseq shows Notch activation yields a 6-fold increase in multi-potent hematopoietic progenitors that follow a developmental trajectory toward T cells with clear similarity to post-natal human thymocytes. We conclude that early mesodermal Notch activation during hematopoietic differentiation is a missing stimulus with broad implications for producing hematopoietic progenitors with definitive characteristics.
- News
For more than 20 years, a team of Boston University scientists have been on a quest to not just figure out how to treat incurable lung diseases, but also how to regenerate damaged lungs so they’re as good as new.
That is the goal of pulmonologist Darrell Kotton and his lab at the Center for Regenerative Medicine (CReM), a joint effort between the University and Boston Medical Center, BU’s primary teaching hospital. By refining their work using sophisticated stem cell technology, Kotton and his team are closer to realizing that vision than ever before.
In two new studies published in Cell Stem Cell, BU researchers detail how they engineered lung stem cells and successfully transplanted them into injured lungs of mice. Two lines of cells targeted two different parts of the lung: the airways, including the trachea and bronchial tubes, and the alveoli, the delicate air sacs that deliver oxygen to the bloodstream. Their findings could eventually lead to new ways for treating lung diseases, including severe cases of COVID-19, emphysema, pulmonary fibrosis, and cystic fibrosis, a disease caused by a genetic mutation.
- Publications
Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)–NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation, and fate determination stages. Tumor and lymphoid compartments sparsely expressed immunosuppressive targets commonly investigated in clinical trials, such as the programmed cell death protein–1/programmed death ligand–1 axis. However, infiltrating myeloid cell types within both primary and metastatic GEP-NETs were enriched for genes encoding other immune checkpoints, including VSIR (VISTA), HAVCR2 (TIM3), LGALS9 (Gal-9), and SIGLEC10. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.
