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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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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.
- News

Announcing
Andrew A. Wilson MD as the Alpha-1 Foundation’s new Scientific Director FOR IMMEDIATE RELEASE November 10, 2022- The Alpha-1 Foundation announces the appointment of Andrew A. Wilson, MD as its new Scientific Director. Dr. Wilson assumes this role with a long-standing passion and commitment to the Alpha-1 community. “On behalf of the Alpha-1 Foundation, I am excited to work with Dr. Wilson to continue the mission-focused work of the Foundation that has been at the forefront of Alpha-1 research for nearly 30 years,” states Scott Santarella, President and CEO of the Alpha-1 Foundation. As a pulmonary and critical care clinician-scientist with a focus on regenerative medicine and stem cell biology, Dr. Wilson’s goal is to advance understanding of and treatment for genetic causes of chronic obstructive pulmonary disease (COPD) and the most common genetic cause of COPD, Alpha-1 Antitrypsin Deficiency (Alpha-1). He has been an active member of the Alpha-1 community since 2006, serving as the head of the Clinical Resource Center (CRC) at Boston University Chobanian & Avedisian School of Medicine, member of the Grant Advisory Committee (GAC) and member of the Research Registry Working Group. Dr Wilson is also site Principal Investigator of the Alpha-1 Biomarkers Consortium (A1BC) study and also of the Alpha-1 Antitrypsin Deficiency Adult Clinical and Genetic Linkage Study at Boston University. Dr. Wilson first became involved with the Alpha-1 Foundation through research during his pulmonary and critical care fellowship at Boston University Chobanian & Avedisian School of Medicine. Interested in developing gene therapies for lung disease, he applied for grant funding from the Alpha-1 Foundation in 2006 and was fortunate to be the recipient of a fellowship grant. Over time, his interest in Alpha-1 grew as he became acquainted with the late John W. Walsh and met Alpha-1 patients at Foundation meetings and events. “I am honored and humbled to have been selected as the new Scientific Director of the Alpha-1 Foundation. Many researchers who are currently working on Alpha-1 research, myself included, probably wouldn’t be doing so if it were not for the support they have received from the Alpha-1 Foundation over the years. In the same vein, having an organized patient community is key since translational research relies upon access to patients with the disease. Researchers must be able to find patients. We are fortunate that Alphas are so enthusiastic and generous in their participation in research. I hope that as Scientific Director I will be able to help the Foundation to advance its mission and work towards a cure for AATD.” In 2012, Dr. Wilson opened the Alpha-1 Center, combining the CRC and the Alpha-1 research program, which has since grown into one of the largest CRCs in the Northeast. The CRC at Boston University Chobanian & Avedisian School of Medicine is highly engaged with the Alpha-1 community through a variety of mechanisms. The Wilson Lab, located at the Center for Regenerative Medicine (CReM) of Boston University/ Boston Medical Center, maintains an active research program focused on Alpha-1. They use patient-derived stem cells, called “induced pluripotent stem cells” or “iPSCs” that can be coaxed to become liver or lung cells in a dish. These cells are used to study how Alpha-1 works in patient cells in the lab and use that system to test potential therapeutics. They also share the cells with other researchers for use in their research efforts directed at developing treatments for Alpha-1 patients. The four core areas of Dr. Wilson’s research are: I) to confirm the clinical significance of the iPSC platform to model in vivo patient biology and demonstrate its potential for testing potential therapeutic agents; II) to better understand the genetic factors and mechanistic drivers that predispose subsets of Alpha-1 patients to develop clinical disease; III) to elucidate the mechanistic contribution of putative COPD susceptibility genes to lung disease pathogenesis; and IV) to develop gene or cell-based therapies for Alpha-1. Dr. Wilson and the Wilson Lab have been actively involved in the Alpha-1 community, participating as a team in the annual Escape to the Cape bike trek on Cape Cod for the past eight years and hosting Alpha-1 support groups from Massachusetts to Maine for visits to CReM many times over the years. These visits have helped inform the CRC about what is important to the patient community and have allowed patients to hear about ongoing research. In some cases, patients have even been able to see their own cells growing in the lab. The Alpha-1 community honored Dr. Wilson in 2014 with the Shillelagh award at the annual Celtic Connection fundraising event to honor his outstanding commitment to Alpha-1
- Publications

Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis
transmembrane conductance regulator anion channel, resulting in significant morbidity and
mortality. The progress in elucidating the role of CFTR using established animal and cellbased
models led to the recent discovery of effective modulators for most individuals with CF.
However, a subset of individuals with CF do not respond to these modulators and there is an
urgent need to develop novel therapeutic strategies. In this study, we generate a panel of
airway epithelial cells using induced pluripotent stem cells from individuals with common or
rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure
CFTR function we adapt two established in vitro assays for use in induced pluripotent stem
cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as
well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect
genotype-specific differences in CFTR baseline function and response to CFTR modulators.
These results demonstrate the potential of the human induced pluripotent stem cell platform
as a research tool to study CF and in particular accelerate therapeutic development for CF
caused by rare variants.
- Publications

SUMMARY
Liver damage and an exacerbated inflammatory response are hallmarks of Ebola virus (EBOV) infection. Little is known about the
intrinsic response to infection in human hepatocytes and their contribution to inflammation. Here, we present an induced pluripotent
stem cell (iPSC)-derived hepatocyte-like cell (HLC) platform to define the hepato-intrinsic response to EBOV infection.We used this platform
to show robust EBOV infection, with characteristic ultrastructural changes and evidence for viral replication. Transcriptomics analysis
revealed a delayed response with minimal early transcriptomic changes, followed by a general downregulation of hepatic function
and upregulation of interferon signaling, providing a potential mechanism by which hepatocytes participate in disease severity and liver
damage. Using RNA-fluorescence in situ hybridization (FISH), we showed that IFNB1 and CXCL10 were mainly expressed in non-infected
bystander cells. We did not observe an inflammatory signature during infection. In conclusion, iPSC-HLCs are an immune competent
platform to study responses to EBOV infection.