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Article ; Online: scTOP: physics-inspired order parameters for cellular identification and visualization.

Yampolskaya, Maria / Herriges, Michael J / Ikonomou, Laertis / Kotton, Darrell N / Mehta, Pankaj

2023 Volume 150, Issue 21

Abstract: Advances in single-cell RNA sequencing provide an unprecedented window into cellular identity. The abundance of data requires new theoretical and computational frameworks to analyze the dynamics of differentiation and integrate knowledge from cell ... ...

Abstract	Advances in single-cell RNA sequencing provide an unprecedented window into cellular identity. The abundance of data requires new theoretical and computational frameworks to analyze the dynamics of differentiation and integrate knowledge from cell atlases. We present 'single-cell Type Order Parameters' (scTOP): a statistical, physics-inspired approach for quantifying cell identity given a reference basis of cell types. scTOP can accurately classify cells, visualize developmental trajectories and assess the fidelity of engineered cells. Importantly, scTOP does this without feature selection, statistical fitting or dimensional reduction (e.g. uniform manifold approximation and projection, principle components analysis, etc.). We illustrate the power of scTOP using human and mouse datasets. By reanalyzing mouse lung data, we characterize a transient hybrid alveolar type 1/alveolar type 2 cell population. Visualizations of lineage tracing hematopoiesis data using scTOP confirm that a single clone can give rise to multiple mature cell types. We assess the transcriptional similarity between endogenous and donor-derived cells in the context of murine pulmonary cell transplantation. Our results suggest that physics-inspired order parameters can be an important tool for understanding differentiation and characterizing engineered cells. scTOP is available as an easy-to-use Python package.
MeSH term(s)	Animals ; Humans ; Mice ; Cell Differentiation/genetics ; Lung ; Single-Cell Analysis/methods ; Sequence Analysis, RNA/methods
Language	English
Publishing date	2023-11-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.201873
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Article ; Online: Epithelial Stem and Progenitor Cells in Lung Repair and Regeneration.

Alysandratos, Konstantinos-Dionysios / Herriges, Michael J / Kotton, Darrell N

Annual review of physiology

2020 Volume 83, Page(s) 529–550

Abstract: The mammalian lung epithelium is composed of a wide array of specialized cells that have adapted to survive environmental exposure and perform the tasks necessary for respiration. Although the majority of these cells are remarkably quiescent during adult ...

Abstract	The mammalian lung epithelium is composed of a wide array of specialized cells that have adapted to survive environmental exposure and perform the tasks necessary for respiration. Although the majority of these cells are remarkably quiescent during adult lung homeostasis, a growing body of literature has demonstrated the capacity of these epithelial lineages to proliferate in response to injury and regenerate lost or damaged cells. In this review, we focus on the regionally distinct lung epithelial cell types that contribute to repair after injury, and we address current controversies regarding whether elite stem cells or frequent facultative progenitors are the predominant participants. We also shed light on the newly emerging approaches for exogenously generating similar lung epithelial lineages from pluripotent stem cells.
MeSH term(s)	Animals ; Cell Differentiation/physiology ; Cell Lineage/physiology ; Epithelial Cells/cytology ; Homeostasis/physiology ; Humans ; Lung/cytology ; Lung/physiology ; Regeneration/physiology ; Stem Cells/cytology
Language	English
Publishing date	2020-10-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	207933-1
ISSN	1545-1585 ; 0066-4278
ISSN (online)	1545-1585
ISSN	0066-4278
DOI	10.1146/annurev-physiol-041520-092904
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Article ; Online: CoSpar identifies early cell fate biases from single-cell transcriptomic and lineage information.

Wang, Shou-Wen / Herriges, Michael J / Hurley, Kilian / Kotton, Darrell N / Klein, Allon M

Nature biotechnology

2022 Volume 40, Issue 7, Page(s) 1066–1074

Abstract: A goal of single-cell genome-wide profiling is to reconstruct dynamic transitions during cell differentiation, disease onset and drug response. Single-cell assays have recently been integrated with lineage tracing, a set of methods that identify cells of ...

Abstract	A goal of single-cell genome-wide profiling is to reconstruct dynamic transitions during cell differentiation, disease onset and drug response. Single-cell assays have recently been integrated with lineage tracing, a set of methods that identify cells of common ancestry to establish bona fide dynamic relationships between cell states. These integrated methods have revealed unappreciated cell dynamics, but their analysis faces recurrent challenges arising from noisy, dispersed lineage data. In this study, we developed coherent, sparse optimization (CoSpar) as a robust computational approach to infer cell dynamics from single-cell transcriptomics integrated with lineage tracing. Built on assumptions of coherence and sparsity of transition maps, CoSpar is robust to severe downsampling and dispersion of lineage data, which enables simpler experimental designs and requires less calibration. In datasets representing hematopoiesis, reprogramming and directed differentiation, CoSpar identifies early fate biases not previously detected, predicting transcription factors and receptors implicated in fate choice. Documentation and detailed examples for common experimental designs are available at https://cospar.readthedocs.io/ .
MeSH term(s)	Bias ; Cell Differentiation/genetics ; Cell Lineage/genetics ; Single-Cell Analysis/methods ; Transcriptome/genetics
Language	English
Publishing date	2022-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-022-01209-1
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Article ; Online: The association of sexual orientation with prostate, breast, and cervical cancer screening and diagnosis.

Herriges, Michael J / Pinkhasov, Ruben / Lehavot, Keren / Shapiro, Oleg / Jacob, Joseph M / Sanford, Thomas / Liu, Nick / Bratslavsky, Gennady / Goldberg, Hanan

Cancer causes & control : CCC

2022 Volume 33, Issue 12, Page(s) 1421–1430

Abstract: Purpose: Data on heterogeneity in cancer screening and diagnosis rates among lesbians/gays and bisexuals (LGBs) is lacking. Recent studies showed that LGBs have decreased healthcare utilization compared to heterosexual counterparts. Few studies have ... ...

Abstract	Purpose: Data on heterogeneity in cancer screening and diagnosis rates among lesbians/gays and bisexuals (LGBs) is lacking. Recent studies showed that LGBs have decreased healthcare utilization compared to heterosexual counterparts. Few studies have examined how sexual orientation impacts cancer screening and prevalence. We, therefore, investigated the association between sexual orientation and prevalent sex-specific cancer including prostate (PCa), breast (BC), and cervical (CC) cancer. Methods: This was a cross-sectional survey-based US study, including men and women aged 18 + from the Health Information National Trends Survey (HINTS) database between 2017 and 2019. The primary endpoint was individual-reported prostate, breast, and cervical cancer screening and prevalence rates among heterosexual and LGB men and women. Multivariable logistic regression analyses assessed association of various covariates with undergoing screening and diagnosis of these cancers. Results: Overall, 4,441 and 6,333 heterosexual men and women, respectively, were compared to 225 and 213 LGB men and women, respectively. LGBs were younger and less likely to be screened for PCa, BC, and CC than heterosexuals. A higher proportion of heterosexual women than lesbian and bisexual women were screened for CC with pap smears (95.36% vs. 90.48% and 86.11%, p ≤ 0.001) and BC with mammograms (80.74% vs. 63.81% and 45.37%, p ≤ 0.001). Similarly, a higher proportion of heterosexual men than gay and bisexual men were screened for PCa with PSA blood tests (41.27% vs. 30.53% and 27.58%, p ≤ 0.001). Conclusion: There were more heterosexuals than LGBs screened for CC, BC, and PCa. However, no association between sexual orientation and cancer diagnosis was found. Healthcare professionals should be encouraged to improve cancer screening among LGBs.
MeSH term(s)	Female ; Humans ; Male ; Early Detection of Cancer ; Uterine Cervical Neoplasms/diagnosis ; Uterine Cervical Neoplasms/epidemiology ; Cross-Sectional Studies ; Prostate ; Sexual Behavior
Language	English
Publishing date	2022-09-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1064022-8
ISSN	1573-7225 ; 0957-5243
ISSN (online)	1573-7225
ISSN	0957-5243
DOI	10.1007/s10552-022-01624-4
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Article ; Online: Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice.

Herriges, Michael J / Yampolskaya, Maria / Thapa, Bibek R / Lindstrom-Vautrin, Jonathan / Wang, Feiya / Huang, Jessie / Na, Cheng-Lun / Ma, Liang / Montminy, McKenna M / Bawa, Pushpinder / Villacorta-Martin, Carlos / Mehta, Pankaj / Kotton, Darrell N

Cell stem cell

2023 Volume 30, Issue 9, Page(s) 1217–1234.e7

Abstract: Durable reconstitution of the distal lung epithelium with pluripotent stem cell (PSC) derivatives, if realized, would represent a promising therapy for diseases that result from alveolar damage. Here, we differentiate murine PSCs into self-renewing lung ... ...

Abstract	Durable reconstitution of the distal lung epithelium with pluripotent stem cell (PSC) derivatives, if realized, would represent a promising therapy for diseases that result from alveolar damage. Here, we differentiate murine PSCs into self-renewing lung epithelial progenitors able to engraft into the injured distal lung epithelium of immunocompetent, syngeneic mouse recipients. After transplantation, these progenitors mature in the distal lung, assuming the molecular phenotypes of alveolar type 2 (AT2) and type 1 (AT1) cells. After months in vivo, donor-derived cells retain their mature phenotypes, as characterized by single-cell RNA sequencing (scRNA-seq), histologic profiling, and functional assessment that demonstrates continued capacity of the engrafted cells to proliferate and differentiate. These results indicate durable reconstitution of the distal lung's facultative progenitor and differentiated epithelial cell compartments with PSC-derived cells, thus establishing a novel model for pulmonary cell therapy that can be utilized to better understand the mechanisms and utility of engraftment.
MeSH term(s)	Animals ; Mice ; Epithelial Cells ; Epithelium ; Cell Differentiation ; Cell- and Tissue-Based Therapy ; Pluripotent Stem Cells
Language	English
Publishing date	2023-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2023.07.016
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Article ; Online: Airway stem cell reconstitution by the transplantation of primary or pluripotent stem cell-derived basal cells.

Ma, Liang / Thapa, Bibek R / Le Suer, Jake A / Tilston-Lünel, Andrew / Herriges, Michael J / Berical, Andrew / Beermann, Mary Lou / Wang, Feiya / Bawa, Pushpinder S / Kohn, Anat / Ysasi, Alexandra B / Kiyokawa, Hirofumi / Matte, Taylor M / Randell, Scott H / Varelas, Xaralabos / Hawkins, Finn J / Kotton, Darrell N

Cell stem cell

2023 Volume 30, Issue 9, Page(s) 1199–1216.e7

Abstract: Life-long reconstitution of a tissue's resident stem cell compartment with engrafted cells has the potential to durably replenish organ function. Here, we demonstrate the engraftment of the airway epithelial stem cell compartment via intra-airway ... ...

Abstract	Life-long reconstitution of a tissue's resident stem cell compartment with engrafted cells has the potential to durably replenish organ function. Here, we demonstrate the engraftment of the airway epithelial stem cell compartment via intra-airway transplantation of mouse or human primary and pluripotent stem cell (PSC)-derived airway basal cells (BCs). Murine primary or PSC-derived BCs transplanted into polidocanol-injured syngeneic recipients give rise for at least two years to progeny that stably display the morphologic, molecular, and functional phenotypes of airway epithelia. The engrafted basal-like cells retain extensive self-renewal potential, evident by the capacity to reconstitute the tracheal epithelium through seven generations of secondary transplantation. Using the same approach, human primary or PSC-derived BCs transplanted into NOD scid gamma (NSG) recipient mice similarly display multilineage airway epithelial differentiation in vivo. Our results may provide a step toward potential future syngeneic cell-based therapy for patients with diseases resulting from airway epithelial cell damage or dysfunction.
MeSH term(s)	Humans ; Animals ; Mice ; Pluripotent Stem Cells ; Cell- and Tissue-Based Therapy ; Epithelial Cells ; Epithelium ; Mice, Inbred NOD ; Mice, SCID
Language	English
Publishing date	2023-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2023.07.014
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Article ; Online: Financial Toxicity and Its Association With Prostate and Colon Cancer Screening.

Herriges, Michael J / Shenhav-Goldberg, Rachel / Peck, Juliet I / Bhanvadia, Sumeet K / Morgans, Alicia / Chino, Fumiko / Chandrasekar, Thenappan / Shapiro, Oleg / Jacob, Joseph M / Basnet, Alina / Bratslavsky, Gennady / Goldberg, Hanan

Journal of the National Comprehensive Cancer Network : JNCCN

2022 Volume 20, Issue 9, Page(s) 981–988

Abstract: Background: The term "financial toxicity" or "hardship" is a patient-reported outcome that results from the material costs of cancer care, the psychological impacts of these costs, and the coping strategies that patients use to deal with the strain that ...

Abstract	Background: The term "financial toxicity" or "hardship" is a patient-reported outcome that results from the material costs of cancer care, the psychological impacts of these costs, and the coping strategies that patients use to deal with the strain that includes delaying or forgoing care. However, little is known about the impact of financial toxicity on cancer screening. We examined the effects of financial toxicity on the use of screening tests for prostate and colon cancer. We hypothesized that greater financial hardship would show an association with decreased prevalence of cancer screening. Methods: This cross-sectional survey-based US study included men and women aged ≥50 years from the National Health Interview Survey database from January through December 2018. A financial hardship score (FHS) between 0 and 10 was formulated by summarizing the responses from 10 financial toxicity dichotomic questions (yes or no), with a higher score associated with greater financial hardship. Primary outcomes were self-reported occurrence of prostate-specific antigen (PSA) blood testing and colonoscopy for prostate and colon cancer screening, respectively. Results: Overall, 13,439 individual responses were collected. A total of 9,277 (69.03%) people had undergone colonoscopies, and 3,455 (70.94%) men had a PSA test. White, married, working men were more likely to undergo PSA testing and colonoscopy. Individuals who had not had a PSA test or colonoscopy had higher mean FHSs than those who underwent these tests (0.70 and 0.79 vs 0.47 and 0.61, respectively; P≤.001 for both). Multivariable logistic regression models demonstrated that a higher FHS was associated with a decreased odds ratio for having a PSA test (0.916; 95% CI, 0.867-0.967; P=.002) and colonoscopy (0.969; 95% CI, 0.941-0.998; P=.039). Conclusions: Greater financial hardship is suggested to be associated with a decreased probability of having prostate and colon cancer screening. Healthcare professionals should be aware that financial toxicity can impact not only cancer treatment but also cancer screening.
MeSH term(s)	Colonic Neoplasms/diagnosis ; Colonic Neoplasms/epidemiology ; Cross-Sectional Studies ; Early Detection of Cancer ; Financial Stress ; Humans ; Male ; Mass Screening ; Prostate ; Prostate-Specific Antigen ; Prostatic Neoplasms/diagnosis ; Prostatic Neoplasms/epidemiology
Chemical Substances	Prostate-Specific Antigen (EC 3.4.21.77)
Language	English
Publishing date	2022-09-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2250759-0
ISSN	1540-1413 ; 1540-1405
ISSN (online)	1540-1413
ISSN	1540-1405
DOI	10.6004/jnccn.2022.7036
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Article ; Online: Tbx5 drives

Rankin, Scott A / Steimle, Jeffrey D / Yang, Xinan H / Rydeen, Ariel B / Agarwal, Kunal / Chaturvedi, Praneet / Ikegami, Kohta / Herriges, Michael J / Moskowitz, Ivan P / Zorn, Aaron M

eLife

2021 Volume 10

Abstract: The gene regulatory networks that coordinate the development of the cardiac and pulmonary systems are essential for terrestrial life but poorly understood. The T-box transcription factor Tbx5 is critical for both pulmonary specification and heart ... ...

Abstract	The gene regulatory networks that coordinate the development of the cardiac and pulmonary systems are essential for terrestrial life but poorly understood. The T-box transcription factor Tbx5 is critical for both pulmonary specification and heart development, but how these activities are mechanistically integrated remains unclear. Here using
MeSH term(s)	Aldehyde Dehydrogenase 1 Family/genetics ; Aldehyde Dehydrogenase 1 Family/metabolism ; Animals ; Base Sequence ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks ; Heart/embryology ; Lung/embryology ; Mesoderm/embryology ; Mice ; Retinal Dehydrogenase/genetics ; Retinal Dehydrogenase/metabolism ; Sequence Alignment ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism ; Xenopus/embryology ; Xenopus/genetics ; Xenopus/metabolism ; Xenopus Proteins/genetics ; Xenopus Proteins/metabolism ; Xenopus laevis/genetics ; Xenopus laevis/metabolism
Chemical Substances	T-Box Domain Proteins ; T-box transcription factor 5 ; Xenopus Proteins ; Aldehyde Dehydrogenase 1 Family (EC 1.2.1) ; Aldh1a2 protein, mouse (EC 1.2.1.36) ; Retinal Dehydrogenase (EC 1.2.1.36) ; aldh1a2 protein, Xenopus (EC 1.2.1.36)
Language	English
Publishing date	2021-10-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.69288
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Article ; Online: The Cellular and Physiological Basis for Lung Repair and Regeneration: Past, Present, and Future.

Basil, Maria C / Katzen, Jeremy / Engler, Anna E / Guo, Minzhe / Herriges, Michael J / Kathiriya, Jaymin J / Windmueller, Rebecca / Ysasi, Alexandra B / Zacharias, William J / Chapman, Hal A / Kotton, Darrell N / Rock, Jason R / Snoeck, Hans-Willem / Vunjak-Novakovic, Gordana / Whitsett, Jeffrey A / Morrisey, Edward E

Cell stem cell

2020 Volume 26, Issue 4, Page(s) 482–502

Abstract: The respiratory system, which includes the trachea, airways, and distal alveoli, is a complex multi-cellular organ that intimately links with the cardiovascular system to accomplish gas exchange. In this review and as members of the NIH/NHLBI-supported ... ...

Abstract	The respiratory system, which includes the trachea, airways, and distal alveoli, is a complex multi-cellular organ that intimately links with the cardiovascular system to accomplish gas exchange. In this review and as members of the NIH/NHLBI-supported Progenitor Cell Translational Consortium, we discuss key aspects of lung repair and regeneration. We focus on the cellular compositions within functional niches, cell-cell signaling in homeostatic health, the responses to injury, and new methods to study lung repair and regeneration. We also provide future directions for an improved understanding of the cell biology of the respiratory system, as well as new therapeutic avenues.
MeSH term(s)	Cell Communication ; Lung ; Pulmonary Alveoli ; Stem Cells ; Trachea
Keywords	covid19
Language	English
Publishing date	2020-04-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2020.03.009
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Article ; Online: The in vivo genetic program of murine primordial lung epithelial progenitors.

Nature communications

2020 Volume 11, Issue 1, Page(s) 635

Abstract: Multipotent Nkx2-1-positive lung epithelial primordial progenitors of the foregut endoderm are thought to be the developmental precursors to all adult lung epithelial lineages. However, little is known about the global transcriptomic programs or gene ... ...

Abstract	Multipotent Nkx2-1-positive lung epithelial primordial progenitors of the foregut endoderm are thought to be the developmental precursors to all adult lung epithelial lineages. However, little is known about the global transcriptomic programs or gene networks that regulate these gateway progenitors in vivo. Here we use bulk RNA-sequencing to describe the unique genetic program of in vivo murine lung primordial progenitors and computationally identify signaling pathways, such as Wnt and Tgf-β superfamily pathways, that are involved in their cell-fate determination from pre-specified embryonic foregut. We integrate this information in computational models to generate in vitro engineered lung primordial progenitors from mouse pluripotent stem cells, improving the fidelity of the resulting cells through unbiased, easy-to-interpret similarity scores and modulation of cell culture conditions, including substratum elastic modulus and extracellular matrix composition. The methodology proposed here can have wide applicability to the in vitro derivation of bona fide tissue progenitors of all germ layers.
MeSH term(s)	Animals ; Cell Culture Techniques ; Cell Differentiation ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; Extracellular Matrix/genetics ; Extracellular Matrix/metabolism ; Female ; Germ Layers/embryology ; Germ Layers/metabolism ; Lung/cytology ; Lung/embryology ; Lung/metabolism ; Male ; Mice/embryology ; Mice/genetics ; Mice/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Pluripotent Stem Cells/cytology ; Pluripotent Stem Cells/metabolism ; Signal Transduction ; Thyroid Nuclear Factor 1/genetics ; Thyroid Nuclear Factor 1/metabolism ; Transcriptome ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism
Chemical Substances	Nkx2-1 protein, mouse ; Thyroid Nuclear Factor 1 ; Transforming Growth Factor beta
Language	English
Publishing date	2020-01-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-14348-3
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