Mass measurements during lymphocytic leukemia cell polyploidization decouple cell cycle- and cell size-dependent growth

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 27; pp. 15659 - 15665
• Main Authors: Mu, Luye, Kang, Joon Ho, Olcum, Selim, Payer, Kristofor R., Calistri, Nicholas L., Kimmerling, Robert J., Manalis, Scott R., Miettinen, Teemu P.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07-07-2020
• Subjects: Animals; Biological Sciences; Biosensing Techniques; Cell cycle; Cell Cycle - genetics; Cell Division - genetics; Cell Enlargement; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Cell size; Efficiency; Humans; Leukemia; Leukemia, Lymphoid - genetics; Leukemia, Lymphoid - pathology; Lymphatic leukemia; Metabolism; Mice; Microchannels; Microfluidic Analytical Techniques; Physical Sciences; Plateaus; Polyploidy; transport limitation; cell growth; mass measurement; cell cycle; cell size
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1922197117

Cell size is believed to influence cell growth and metabolism. Consistently, several studies have revealed that large cells have lower mass accumulation rates per unit mass (i.e., growth efficiency) than intermediate-sized cells in the same population. Sizedependent growth is commonly attributed to transport limitations, such as increased diffusion timescales and decreased surface-to-volume ratio. However, separating cell size- and cell cycle-dependent growth is challenging. To address this, we monitored growth efficiency of pseudodiploid mouse lymphocytic leukemia cells during normal proliferation and polyploidization. This was enabled by the development of large-channel suspended microchannel resonators that allow us to monitor buoyant mass of single cells ranging from 40 pg (small pseudodiploid cell) to over 4,000 pg, with a resolution ranging from ∼1% to ∼0.05%. We find that cell growth efficiency increases, plateaus, and then decreases as cell cycle proceeds. This growth behavior repeats with every endomitotic cycle as cells grow into polyploidy. Overall, growth efficiency changes 33% throughout the cell cycle. In contrast, increasing cell mass by over 100-fold during polyploidization did not change growth efficiency, indicating exponential growth. Consistently, growth efficiency remained constant when cell cycle was arrested in G₂. Thus, cell cycle is a primary determinant of growth efficiency. As growth remains exponential over large size scales, our work finds no evidence for transport limitations that would decrease growth efficiency.