Cell-cell communication and secretomes

Models and data analysis of how cells exchange molecules, from tunneling nanotubes and secretomes to tissue-wide signaling maps.

Cell-cell communication Single-cell & spatial omics

Network diagrams of lung cell types connected by ligand-receptor edges in four species, with edge-weight plots. — Mapping cell-cell signaling in the lung. Single-cell expression is matched against a ligand-receptor database to build weighted networks, which are then compared across mouse, rat, pig and human. Source: Raredon et al., Science Advances (2019), CC BY-NC.

The full description of this project, with its approach, findings and figures, is on the Suhail Lab website.

Key papers: (Suhail et al., 2013; Kshitiz et al., 2015; Kshitiz et al., 2019; Kshitiz et al., 2017; Raredon et al., 2019; Afzal et al., 2022; Chiou et al., 2020; Afzal et al., 2025; Du et al., 2024).

References

2025

PNAS

Evidence for coopetition at the maternal–fetal interface shaping placental invasion

Junaid Afzal, Yasir Suhail, Wenqiang Du, Yamin Liu, R. Ramasamy, Z. Liu, Ruchi Goyal, Ashkan Novin, S. Suhail, Jamie Maziarz, Günter P. Wagner, and Kshitiz

Proceedings of the National Academy of Sciences, 2025

Placenta & pregnancy Cell-cell communication Stroma & invasion

2024

Nat Commun

Scar matrix drives Piezo1 mediated stromal inflammation leading to placenta accreta spectrum

Wenqiang Du, Ashkan Novin, Yamin Liu, Junaid Afzal, Yasir Suhail, Shaofei Liu, others, and Kshitiz

Nature Communications, 2024

Placenta & pregnancy Stroma & invasion

2022

Cell Rep

Cardiac ultrastructure inspired matrix induces advanced metabolic and functional maturation of differentiated human cardiomyocytes

Junaid Afzal, Yamin Liu, Wenqiang Du, Yasir Suhail, Pengyu Zong, Jianlin Feng, Visar Ajeti, Wasim A. Sayyad, Joerg Nikolaus, Maya Yankova, Alix C. Deymier, Lixia Yue, and Kshitiz

Cell Reports, 2022

Collaborations

DOI Abs

The vast potential of human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) in preclinical models of cardiac pathologies, precision medicine, and drug screening remains to be fully realized because hiPSC-CMs are immature without adult-like characteristics. Here, we present a method to accelerate hiPSC-CM maturation on a substrate, cardiac mimetic matrix (CMM), mimicking adult human heart matrix ligand chemistry, rigidity, and submicron ultrastructure, which synergistically mature hiPSC-CMs rapidly within 30 days. hiPSC-CMs matured on CMM exhibit systemic transcriptomic maturation toward an adult heart state, are aligned with high strain energy, metabolically rely on oxidative phosphorylation and fatty acid oxidation, and display enhanced redox handling capability, efficient calcium handling, and electrophysiological features of ventricular myocytes. Endothelin-1-induced pathological hypertrophy is mitigated on CMM, highlighting the role of a native cardiac microenvironment in withstanding hypertrophy progression. CMM is a convenient model for accelerated development of ventricular myocytes manifesting highly specialized cardiac-specific functions.

2020

CMBE

Scaffold architecture and matrix strain modulate mesenchymal cell and microvascular growth and development in a time dependent manner

G. Chiou, E. Jui, A. C. Rhea, A. Gorthi, S. Miar, F. M. Acosta, C. Perez, Yasir Suhail, Kshitiz, and Y. Chen

Cellular and Molecular Bioengineering, 2020

Collaborations

2019

PNAS

Dynamic secretome of bone marrow-derived stromal cells reveals a cardioprotective biochemical cocktail

Kshitiz, David D. Ellison, Yasir Suhail, Junaid Afzal, Laura Woo, Onur Kilic, Jeffrey Spees, and Andre Levchenko

Proceedings of the National Academy of Sciences of the United States of America, 2019

Cell-cell communication

DOI Abs

Transplanted stromal cells have demonstrated considerable promise as therapeutic agents in diverse disease settings. Paracrine signaling can be an important mediator of these therapeutic effects at the sites of acute or persistent injury and inflammation. As many stromal cell types, including bone marrow-derived stromal cells (BMSCs), display tissue-specific responses, there is a need to explore their secretory dynamics in the context of tissue and injury type. Paracrine signals are not static, and could encode contextual dynamics in the kinetic changes of the concentrations of the secreted ligands. However, precise measurement of dynamic and context-specific cellular secretory signatures, particularly in adherent cells, remains challenging. Here, by creating an experimental and computational analysis platform, we reconstructed dynamic secretory signatures of cells based on a very limited number of time points. By using this approach, we demonstrate that the secretory signatures of CD133-positive BMSCs are uniquely defined by distinct biological contexts, including signals from injured cardiac cells undergoing oxidative stress, characteristic of cardiac infarction. Furthermore, we show that the mixture of recombinant factors reproducing the dynamics of BMSC-generated secretion can mediate a highly effective rescue of cells injured by oxidative stress and an improved cardiac output. These results support the importance of the dynamic multifactorial paracrine signals in mediating remedial effects of stromal stem cells, and pave the way for stem cell-inspired cell-free treatments of cardiac and other injuries.
Sci Adv

Single-cell connectomic analysis of adult mammalian lungs

Micha Sam Brickman Raredon, Taylor Sterling Adams, Yasir Suhail, Jonas Christian Schupp, Sergio Poli, Nir Neumark, Katherine L. Leiby, Allison Marie Greaney, Yifan Yuan, Corey Horien, George Linderman, Alexander J. Engler, Daniel J. Boffa, Yuval Kluger, Ivan O. Rosas, Andre Levchenko, Naftali Kaminski, and Laura E. Niklason

Science Advances, 2019

Single-cell & spatial omics Cell-cell communication

DOI Abs

Efforts to decipher chronic lung disease and to reconstitute functional lung tissue through regenerative medicine have been hampered by an incomplete understanding of cell-cell interactions governing tissue homeostasis. Because the structure of mammalian lungs is highly conserved at the histologic level, we hypothesized that there are evolutionarily conserved homeostatic mechanisms that keep the fine architecture of the lung in balance. We have leveraged single-cell RNA sequencing techniques to identify conserved patterns of cell-cell cross-talk in adult mammalian lungs, analyzing mouse, rat, pig, and human pulmonary tissues. Specific stereotyped functional roles for each cell type in the distal lung are observed, with alveolar type I cells having a major role in the regulation of tissue homeostasis. This paper provides a systems-level portrait of signaling between alveolar cell populations. These methods may be applicable to other organs, providing a roadmap for identifying key pathways governing pathophysiology and informing regenerative efforts.

2017

Circulation

A Universal Secretory Signature: Analysis of Dynamic Secretomes of Stem Cells Types Uncovers a Common Cytoprotective Paracrine Signature Protecting Cardiac Cells From Reperfusion Induced Stress

Kshitiz, David D. Ellison, Yasir Suhail, Junaid Afzal, and Andre Levchenko

Circulation, 2017

Cell-cell communication

2015

Integr Biol

Control of the interface between heterotypic cell populations reveals the mechanism of intercellular transfer of signaling proteins

Kshitiz, Junaid Afzal, Yasir Suhail, Eun Hyun Ahn, Ruchi Goyal, Maimon E. Hubbi, Qasim Hussaini, David D. Ellison, Jatinder Goyal, Benjamin Nacev, Deok Ho Kim, Justin Ho Lee, Sam Frankel, Kevin Gray, Rashmi Bankoti, Andy J. Chien, and Andre Levchenko

Integrative Biology (United Kingdom), 2015

Cell-cell communication Stroma & invasion

DOI Abs

Direct intercellular transfer of cellular components is a recently described general mechanism of cell-cell communication. It is a more non-specific mode of intercellular communication that is not actively controlled by the participating cells. Though membrane bound proteins and small non-protein cytosolic components have been shown to be transferred between cells, the possibility of transfer of cytosolic proteins has not been clearly established, and its mechanism remains unexplained. Using a cell-cell pair of metastatic melanoma and endothelial cells, known to interact at various stages during cancer progression, we show that cytosolic proteins can indeed be transferred between heterotypic cells. Using precise relative cell patterning we provide evidence that this transfer depends on extent of the interface between heterotypic cell populations. This result is further supported by a mathematical model capturing various experimental conditions. We further demonstrate that cytosolic protein transfer can have important functional consequences for the tumor-stroma interactions, e.g., in heterotypic transfer of constitutively activated BRAF, a common melanoma associated mutation, leading to an enhanced activation of the downstream MAPK pathway. Our results suggest that cytosolic protein transfer can have important consequences for regulation of processes involving physical co-location of heterotypic cell types, particularly in invasive cancer growth.

2013

Bull Math Biol

Modeling Intercellular Transfer of Biomolecules Through Tunneling Nanotubes

Yasir Suhail, Kshitiz, Justin Lee, Mark Walker, Deok Ho Kim, Matthew D. Brennan, Joel S. Bader, and Andre Levchenko

Bulletin of Mathematical Biology, 2013

Cell-cell communication Methods & models

DOI Abs

Tunneling nanotubes (TNTs) have previosly been observed as long and thin transient structures forming between cells and intercellular protein transfer through them has been experimentally verified. It is hypothesized that this may be a physiologically important means of cell-cell communication. This paper attempts to give a simple model for the rates of transfer of molecules across these TNTs at different distances. We describe the transfer of both cytosolic and membrane bound molecules between neighboring populations of cells and argue how the lifetime of the TNT, the diffusion rate, distance between cells, and the size of the molecules may affect their transfer. The model described makes certain predictions and opens a number of questions to be explored experimentally. © 2013 Society for Mathematical Biology.