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Spheroid Derived Lung Cells – An alternative to MSCs for Lung Regeneration?

Review of “Adult Lung Spheroid Cells Contain Progenitor Cells and Mediate Regeneration in Rodents with Bleomycin-Induced Pulmonary Fibrosis” from Stem Cells Translational Medicine by Stuart P. Atkinson

Stem cell-based therapeutics for lung injury and disease has generally relied on the infusion of mesenchymal stem cells (MSCs) derived from various sources. However, the identification of various types of lung-resident stem cells has prompted studies into their isolation, cultivation, and characterization, with a view to enhanced therapeutic effect over and above non-lung MSCs [1]. A new study from the laboratory of Ke Cheng (North Carolina State University, USA) has now described a new culture strategy which has allowed the amplification of lung stem cells with the ability to promote recovery in a mouse model of lung injury [2].

The study used three-dimensional spheroid growth to quickly amplify the number of lung stem/progenitor cells taken from samples of healthy human lung tissues. Each spheroid consisted of lung progenitor clusters (cells expressed Pro-SPC, CCSP, p63 and KRT5) surrounded by supporting stromal-like cells as is normally observed in the lung stem cell niche. Following dissociation of the spheroids, and without the need for cell sorting, two-dimensional (adhesive) culture generated a large amount of lung spheroid cells (LSCs) which remained phenotypically similar to the spheroid progenitors and distinct to that of MSCs. LSCs expressed high levels of factors which can enhance cell survival and proliferation and boost angiogenesis, and after Matrigel implantation, differentiated into alveoli-like structures and acquired mature lung epithelial phenotypes.

But how do LSCs compare to the tried and tested MSCs? Using a mouse model of pulmonary fibrosis (PF), intravenous infusion of LSCs reduced the normally observed fibrous thickening and tissue infiltration via a reduction in the amount of apoptotic cells, an increase in angiogenesis, and a decrease in the expression of fibrotic gene expression. Encouragingly, the study found a greater reduction in fibrotic thickening and infiltration for LSC infusion when compared to adipose tissue MSC treatment (See figure C and D respectively), so suggesting that LSCs may represent an exciting new option for the treatment of lung injury/disease through a potent paracrine-based mechanism.

MSCs are a well-understood and easy-to-handle stem cell source with a range of pro-regenerative attributes and clinical advantages, but are LSCs a viable option for lung regeneration? The authors note that using their culture system, small samples can yield cell numbers suitable for autologous and allogeneic applications with no need for laborious and expensive cell sorting, while the lack of tumors or ectopic tissues after infusion in mice points to their safety. Encouragingly, the authors also noted success in generating LSCs from mice and human patients with PF and they hope to study their regenerative potential of these LSCs in the very near future.


  1. Kotton DN and Morrisey EE Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat Med 2014;20:822-832.
  2. Henry E, Cores J, Hensley MT, et al. Adult Lung Spheroid Cells Contain Progenitor Cells and Mediate Regeneration in Rodents With Bleomycin-Induced Pulmonary Fibrosis. Stem Cells Transl Med 2015;4:1265-1274.