Aging-induced changes in lymphatic muscle cell transcriptomes are associated with reduced pumping of peripheral collecting lymphatic vessels in mice

Pin-Ji Lei; Katarina J Ruscic; Kangsan Roh; Johanna J Rajotte; Meghan J O'Melia; Echoe M Bouta; Marla Marquez; Ethel R Pereira; Ashwin S Kumar; Mohammad S Razavi; Hengbo Zhou; Lutz Menzel; Liqing Huang; Heena Kumra; Mark Duquette; Peigen Huang; James W Baish; Lance L Munn; Natasza A Kurpios; Jessalyn M Ubellacker; Timothy P Padera

doi:10.1016/j.devcel.2024.12.010

Aging-induced changes in lymphatic muscle cell transcriptomes are associated with reduced pumping of peripheral collecting lymphatic vessels in mice

Dev Cell. 2024 Dec 19:S1534-5807(24)00732-9. doi: 10.1016/j.devcel.2024.12.010. Online ahead of print.

Authors

Pin-Ji Lei¹, Katarina J Ruscic², Kangsan Roh³, Johanna J Rajotte⁴, Meghan J O'Melia¹, Echoe M Bouta¹, Marla Marquez¹, Ethel R Pereira¹, Ashwin S Kumar⁵, Mohammad S Razavi¹, Hengbo Zhou⁶, Lutz Menzel¹, Liqing Huang⁷, Heena Kumra¹, Mark Duquette¹, Peigen Huang¹, James W Baish⁸, Lance L Munn¹, Natasza A Kurpios⁷, Jessalyn M Ubellacker⁹, Timothy P Padera¹⁰

Affiliations

¹ Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
² Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
³ Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Corrigan-Minehan Heart Center and Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁴ Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Roswell Park Cancer Institute, Buffalo, NY 14203, USA.
⁵ Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁶ Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁷ Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
⁸ Department of Biomedical Engineering, Bucknell University, Lewisburg, PA 17837, USA.
⁹ Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
¹⁰ Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected].

PMID: 39731913
DOI: 10.1016/j.devcel.2024.12.010

Abstract

Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the gene transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas-including LMCs-of peripheral collecting lymphatic vessels from mice across the lifespan. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and identified a proinflammatory microenvironment that suppresses the contractile apparatus in LMCs from advanced-aged mice. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to improve lymphatic vessel function.

Keywords: aging; ion channel; lymphatic muscle cells; lymphatic pumping; single-cell RNA sequencing.