Science - USA (2022-01-07)

INSIGHTS | PERSPECTIVES

GRAPHIC: KELLIE HOLOSKI/

SCIENCE

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sity in the polar region with migrations of
diverse warmer-water species, while wiping
out less-diverse but distinct polar endemics.
This domino effect of species displace-
ments leads to the prediction that warm-
ing may reduce tropical diversity while
causing extinction for polar endemic spe-
cies (see the figure). Although the real-
ity is certainly far more complex, growing
evidence at multiple time scales suggests
that the broad brushstrokes of this simple
picture are correct. Indeed, warming-in-
duced tropical biodiversity losses have been
reported in modern marine biological rec-
ords ( 11 ), and they are largely consistent
with reports from paleobiology (12, 13).
Different areas of the tropics may re-
spond differently. Although the tropical
oceans contain the warmest and lowest O 2 -
containing waters, the two extremes are not
ubiquitous in all tropical oceans. The eastern
tropical Pacific may contain very low O 2 be-
low the surface but is relatively cool for the
tropics, allowing replacement with warmer-
water fishes. Such replacement may not be
possible on the other side of the tropical
Pacific, where the waters are warmer. In ad-
dition, this climate change–triggered loss of
tropical diversity may not be confined to the
oceans, as the exceedance of thermal toler-
ance on land is also projected to be the most
severe in the tropics ( 14 ). The climate-driven
reshuffling of the ecosystem structure will be
profound. The findings of Salvatteci et al. are
the latest addition to the emerging evidence
that a warmer future will alter ecological
communities in tropical oceans, which dis-
proportionally affect developing countries,
where the reliance on small-scale fishing is
especially high. j

REFERENCES AND NOTES

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7. W. W. L. Cheung, D. Pauly, in Explaining Ocean Warming:
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8. S. Lefevre, D. J. McKenzie, G. E. Nilsson, Glob. Change
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11. C. Chaudhary, A. J. Richardson, D. S. Schoeman, M. J.
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12. W. Kiessling, C. Simpson, B. Beck, H. Mewis, J. M.
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10.1126/science.abn2384

E ngineers point the way toward

more complex and homogeneous intestinal organoids

DEVELOPMENTAL BIOLOGY

Setting boundaries

for tissue patterning

By T yler R. Huycke and Zev J. Gartner

T

he functional units of structure in the

small intestine are crypts and villi,

where compartmentalized zones of

stem, progenitor, and differentiated

cell types carry out essential roles in

tissue homeostasis, nutrient absorp-

tion, and barrier maintenance. These struc-

tures can be modeled in vitro by using organ-

oids that self-organize from isolated crypts

or intestinal stem cells (ISCs). However,

organoids suffer from heterogeneity in size,

geometric patterning, cell type composition,

and overall morphology, which impairs re-

producibility and limits their applications.

On page 40 of this issue, Gjorevski et al. ( 1 )

report the use of multiple bioengineering

strategies to generate more structurally com-

plex and reproducible intestinal organoids.

They find that tissue geometry instructs or-

ganoid self-organization into patterned crypt

and villus domains by influencing regional

differences in cell crowding and downstream

Yes-associated protein (YAP)–Notch signal-

ing. These findings add to evidence that tis-

sue structure is sufficient to specify cell state

and behavior.

To spatially control organoid crypt for-

mation, the authors use photochemistry to

pattern regions of soft and stiff extracellular

matrix (ECM) under the basal surface of the

epithelium. Organoids bud precisely in the

softened regions into crypt-like domains that

harbor ISCs and Paneth cells (secretory cells

located between ISCs), whereas the nonbud-

ding regions resemble villus-like domains

with differentiated absorptive cells. Gjorevski

et al. reasoned that altering substrate geom-

etry might act analogously to altering sub-

strate stiffness to pattern cell states within

the intestinal epithelium. To test this idea,

they use a microscale engineering approach

originally designed to study branching in

the mammary epithelium ( 2 ), which involves

seeding organoids in pill-shaped cavities

within a collagen hydrogel. They find that

ISCs localize to the curved ends of the cavi-

ties, whereas differentiated cells localize to

the flat sides. This demonstrates that simple

Tissue form

Cell state

Dierentiated cells

Paneth cells

Transit-

amplifying cells

Intestinal

stem cells

Traditional intestinal

organoids

Stochastic cell patterning

in traditional organoids

Photopatterned

organoids

Geometry-defined

organoids

Topographically defined

organoids

Deterministic cell

patterning

Time

Time

Crypt

geometry

Dierential

cell crowding

and YAP-Notch

signaling

Cell and

tissue

mechanics

Paneth cell

localization

YA P o n

Notch off

Stretch-

dependent

YA P off

Notch on

Villus

domain

Crypt

domain

26 7 JANUARY 2022 • VOL 375 ISSUE 6576

Engineering intestinal organoids

Methods to engineer more complex and homogeneously patterned organoids reveal how cell patterning arises.

Key parameters in defining cell state are differential cell crowding and Yes-associated protein (YAP)–Notch

signaling. A dynamic reciprocity exists between tissue geometry and cell state that patterns intestinal organoids.