Emergence of division of labor in tissues through cell interactions and spatial cues

Miri Adler, Noa Moriel, Aleksandrina Goeva, Inbal Avraham-Davidi, Simon Mages, Taylor S. Adams, Naftali Kaminski, Evan Z. Macosko, Aviv Regev*, Ruslan Medzhitov*, Mor Nitzan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Most cell types in multicellular organisms can perform multiple functions. However, not all functions can be optimally performed simultaneously by the same cells. Functions incompatible at the level of individual cells can be performed at the cell population level, where cells divide labor and specialize in different functions. Division of labor can arise due to instruction by tissue environment or through self-organization. Here, we develop a computational framework to investigate the contribution of these mechanisms to division of labor within a cell-type population. By optimizing collective cellular task performance under trade-offs, we find that distinguishable expression patterns can emerge from cell-cell interactions versus instructive signals. We propose a method to construct ligand-receptor networks between specialist cells and use it to infer division-of-labor mechanisms from single-cell RNA sequencing (RNA-seq) and spatial transcriptomics data of stromal, epithelial, and immune cells. Our framework can be used to characterize the complexity of cell interactions within tissues.

Original languageAmerican English
Article number112412
JournalCell Reports
Volume42
Issue number5
DOIs
StatePublished - 30 May 2023

Bibliographical note

Funding Information:
We thank Uri Alon, Johanna Klughammer, and members of our labs for meaningful discussions. This work was supported by the EMBO Long-Term Fellowship (ALTF 304-2019), the Zuckerman STEM Leadership program, and the Israel National Postdoctoral Award Program for Advancing Women in Science (M.A.); the Israeli Council for Higher Education Ph.D. fellowship (N.M.) and the Center for Interdisciplinary Data Science Research at the Hebrew University of Jerusalem (N.M. and M.N.); a DFG research fellowship (MA 9108/1-1) (S.M.); NIH grants R01HL127349, U01HL145567, and U01HL122626 and the Three Lakes Foundation (N.K.); the BroadIgnite philanthropic grant (A.G.); the Howard Hughes Medical Institute (A.R. and R.M.); the Klarman Cell Observatory (A.R.); the Blavatnik Family Foundation (R.M.); a grant from the NIH AI144152 (R.M.); and an Azrieli Foundation Early Career Faculty Fellowship, Alon Fellowship, ISF Research Grant (1079/21), and the European Union (ERC, DecodeSC, 101040660) (M.N.). Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. Conceptualization, M.A. N.M. A.G. A.R. R.M. and M.N.; methodology, M.A. N.M. A.G. and M.N.; software, M.A. N.M. S.M. and M.N.; validation, M.A. N.M. and A.R.; formal analysis, M.A. N.M. and A.G.; investigation, I.A.-D. T.S.A. and N.K.; resources, I.A.-D. T.S.A. N.K. A.R. and M.N.; writing – original draft, M.A. N.M. A.G. A.R. R.M. and M.N.; writing – review & editing, all authors; visualization, M.A. N.M. and A.G.; supervision, E.Z.M. A.R. R.M. and M.N. N.K. has served as a consultant to Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Optikira, Astra Zeneca, RohBar, Veracyte, Augmanity, CSL Behring, Galapagos, Gilead, Arrowhead, and Thyron over the last 3 years and reports equity in Pliant and Thyron; a grant from Veracyte, Boehringer Ingelheim, BMS; and non-financial support from MiRagen and Astra Zeneca. N.K. has intellectual property (IP) on novel biomarkers and therapeutics in idiopathic pulmonary fibrosis (IPF) licensed to Biotech. E.Z.M. is a consultant for Curio Biosciences, Inc. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was an SAB member of Thermo Fisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics, and Asimov until July 31, 2020. Beginning August 1, 2020, A.R. has been an employee of Genentech and has equity in Roche.

Funding Information:
N.K. has served as a consultant to Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Optikira, Astra Zeneca, RohBar, Veracyte, Augmanity, CSL Behring, Galapagos, Gilead, Arrowhead, and Thyron over the last 3 years and reports equity in Pliant and Thyron; a grant from Veracyte, Boehringer Ingelheim, BMS; and non-financial support from MiRagen and Astra Zeneca. N.K. has intellectual property (IP) on novel biomarkers and therapeutics in idiopathic pulmonary fibrosis (IPF) licensed to Biotech. E.Z.M. is a consultant for Curio Biosciences, Inc. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was an SAB member of Thermo Fisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics, and Asimov until July 31, 2020. Beginning August 1, 2020, A.R. has been an employee of Genentech and has equity in Roche.

Funding Information:
We thank Uri Alon, Johanna Klughammer, and members of our labs for meaningful discussions. This work was supported by the EMBO Long-Term Fellowship ( ALTF 304-2019 ), the Zuckerman STEM Leadership program, and the Israel National Postdoctoral Award Program for Advancing Women in Science (M.A.); the Israeli Council for Higher Education Ph.D. fellowship (N.M.) and the Center for Interdisciplinary Data Science Research at the Hebrew University of Jerusalem (N.M. and M.N.); a DFG research fellowship ( MA 9108/1-1 ) (S.M.); NIH grants R01HL127349 , U01HL145567 , and U01HL122626 and the Three Lakes Foundation (N.K.); the BroadIgnite philanthropic grant (A.G.); the Howard Hughes Medical Institute (A.R. and R.M.); the Klarman Cell Observatory (A.R.); the Blavatnik Family Foundation (R.M.); a grant from the NIH AI144152 (R.M.); and an Azrieli Foundation Early Career Faculty Fellowship, Alon Fellowship, ISF Research Grant ( 1079/21 ), and the European Union ( ERC , DecodeSC, 101040660 ) (M.N.). Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them.

Publisher Copyright:
© 2023

Keywords

  • CP: Developmental biology
  • Pareto optimality
  • division of labor
  • enterocytes
  • fibroblasts
  • lateral inhibition
  • macrophages
  • morphogens
  • self-organization

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