Science - USA (2020-05-01)

COVID-19, although in this work it was not
possible to definitively determine the impact
of each intervention. Much further work is
required to determine how to balance optimally
the expected positive effect on public health
with the negative impact on freedom of move-
ment, the economy, and society at large.

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ACKNOWLEDGMENTS
We thank all individuals who are collecting epidemiological data of
the COVID-19 outbreak around the world.Funding:H.T., O.G.P.,
and M.U.G.K. acknowledge support from the Oxford Martin School.
M.U.G.K. is supported by a Branco Weiss Fellowship. B.G. is
supported by a Universities of Academic Excellence Scholarship
Program of the Secretariat for Higher Education, Science,
Technology, and Innovation of the Republic of Ecuador (grant no.
ARSEQ-BEC-003163-2017). N.R.F. is supported by a Sir Henry Dale
Fellowship. W.P.H. is supported by the National Institute of General
Medical Sciences (grant no. U54GM088558). The funders had no
role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.Author contributions:
M.U.G.K., O.G.P., and S.V.S. developed the idea and research.
M.U.G.K. and S.V.S. wrote the first draft of the manuscript, and all
other authors discussed results and edited the manuscript.
M.U.G.K., B.G., S.V.S., D.M.P., and the Open COVID-19 Data Working
Group collected and validated epidemiological data. R.L. and
M.U.G.K. collected intervention data. C.-H.Y., B.K., and S.V.S.
collected and processed human mobility data.Competing interests:
S.V.S. is on the advisory board for BioFire Diagnostics Trend
Surveillance, which includes paid consulting. A.V. reports past grants
and personal fees from Metabiota Inc. outside of the submitted work.

The remaining authors declare no competing interests.Data and

materials availability:Code and data are available on the following

GitHub repository: https://github.com/Emergent-Epidemics/

covid19_cordon and permanently on Zenodo ( 25 ).

SUPPLEMENTARY MATERIALS

science.sciencemag.org/content/368/6490/493/suppl/DC1

Materials and Methods

Supplementary Text

Figs. S1 to S9

Tables S1 and S2

List of Members of the Open COVID-19 Data Working Group

References ( 26 – 39 )

3 March 2020; accepted 23 March 2020

Published online 25 March 2020

10.1126/science.abb4218

TISSUE REGENERATION

Regenerative potential of prostate luminal cells

revealed by single-cell analysis

Wouter R. Karthaus^1 *, Matan Hofree^2 *, Danielle Choi^1 , Eliot L. Linton^1 , Mesruh Turkekul^7 ,

Alborz Bejnood^2 , Brett Carver^1 , Anuradha Gopalan^1 , Wassim Abida^1 , Vincent Laudone^1 , Moshe Biton^2 ,

Ojasvi Chaudhary^3 , Tianhao Xu^3 , Ignas Masilionis^3 , Katia Manova^7 , Linas Mazutis^3 , Dana Pe’er3,6,

Aviv Regev2,4,5†, Charles L. Sawyers1,4†

Androgen deprivation is the cornerstone of prostate cancer treatment. It results in involution of

the normal gland to ~90% of its original size because of the loss of luminal cells. The prostate

regenerates when androgen is restored, a process postulated to involve stem cells. Using single-cell

RNA sequencing, we identified a rare luminal population in the mouse prostate that expresses

stemlike genes (Sca1+andPsca+) and a large population of differentiated cells (Nkx3.1+,Pbsn+). In

organoids and in mice, both populations contribute equally to prostate regeneration, partly through

androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a

paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated

and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after

androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal

cells, not just by rare stem cells.

E

pithelial tissue homeostasis, at steady

state or in response to injury, depends

on replenishment of cells by stem cell

populations. Whether such stem cells

are rare cells with multilineage and self-

renewal potential or if they are recruited from

lineage-committed cells (facultative stem cells)

varies across different tissues ( 1 ). The normal

prostate gland includes luminal epithelial cells,

basal epithelial cells, and rare neuroendocrine

cells surrounded by stroma and vasculature

( 2 , 3 ). After surgical or pharmacological cas-

tration (a common treatment for advanced

prostate cancer), the prostate involutes to

~90% of its original size, mainly because of

the loss of luminal epithelial cells ( 3 , 4 ). Upon

exogenous addition of testosterone, the mouse

prostate fully regenerates within 4 weeks,

which has sparked efforts to identify an un-

derlying stem cell population ( 4 – 6 ). To pro-

vide further insights into this matter, we

used single-cell RNA seq (scRNA-seq) to char-

acterize cell types in the murine and human

prostate and track their gene expression pro-

grams during castration and, in mouse, during

regeneration.

Results

To characterize the different cell populations

of the prostate, we collected droplet-based

scRNA-seq profiles from 13,398 cells from

the mouse prostate (concentrating initially

on the anterior lobe) without fluorescence-

activated cell sorting (FACS). We identified

15 distinct cell subsets by unsupervised graph

clustering (Fig. 1A and fig. S1, a and b), with

further partitioning to 22 subsets, spanning

6 epithelial and 16 nonepithelial subsets (figs.

S1, d to f, and S2). To ensure adequate repre-

sentation of all epithelial cells, we also profiled

Epcam-positive and -negative cells isolated

by FACS, but found a substantial reduction

in quality and near-complete loss of two lu-

minal populations (fig. S1c). We therefore

conducted all subsequent experiments using

SCIENCEsciencemag.org 1 MAY 2020•VOL 368 ISSUE 6490 497

(^1) Human Oncology and Pathogenesis Program, Memorial
Sloan Kettering Cancer Center, New York, NY 10065, USA.
(^2) Klarman Cell Observatory, Broad Institute of Massachusetts
Institute of Technology and Harvard University, Cambridge,
MA 02142, USA.^3 Program for Computational and Systems
Biology, Sloan Kettering Institute, Memorial Sloan Kettering
Cancer Center, New York, NY 10065, USA.^4 Howard Hughes
Medical Institute, Chevy Chase, MD 20815, USA.^5 Koch
Institute of Integrative Cancer Research, Department of
Biology, Massachusetts Institute of Technology, Cambridge,
MA 02139, USA.^6 Parker Institute for Cancer Immunotherapy,
Memorial Sloan Kettering Cancer Center, New York, NY
10065, USA.^7 Molecular Cytology, Memorial Sloan Kettering
Cancer Center, New York, NY 10065, USA.
*These authors contributed equally to this work.
†Corresponding author. Email: [email protected] (A.R.);
[email protected] (C.L.S)
RESEARCH | RESEARCH ARTICLES