Nolen-Walston R D, Kim C F, Mazan M R, Ingenito E P, Gruntman A M, Tsai L, Boston R, Woolfenden A E, Jacks T, Hoffman A M
Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts 01536, USA.
Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1158-65. doi: 10.1152/ajplung.00298.2007. Epub 2008 Mar 28.
Organ regeneration in mammals is hypothesized to require a functional pool of stem or progenitor cells, but the role of these cells in lung regeneration is unknown. Whereas postnatal regeneration of alveolar tissue has been attributed to type II alveolar epithelial cells (AECII), we reasoned that bronchioalveolar stem cells (BASCs) have the potential to contribute substantially to this process. To test this hypothesis, unilateral pneumonectomy (PNX) was performed on adult female C57/BL6 mice to stimulate compensatory lung regrowth. The density of BASCs and AECII, and morphometric and physiological measurements, were recorded on days 1, 3, 7, 14, 28, and 45 after surgery. Vital capacity was restored by day 7 after PNX. BASC numbers increased by day 3, peaked to 220% of controls (P<0.05) by day 14, and then returned to baseline after active lung regrowth was complete, whereas AECII cell densities increased to 124% of baseline (N/S). Proliferation studies revealed significant BrdU uptake in BASCs and AECII within the first 7 days after PNX. Quantitative analysis using a systems biology model was used to evaluate the potential contribution of BASCs and AECII. The model demonstrated that BASC proliferation and differentiation contributes between 0 and 25% of compensatory alveolar epithelial (type I and II cell) regrowth, demonstrating that regeneration requires a substantial contribution from AECII. The observed cell kinetic profiles can be reconciled using a dual-compartment (BASC and AECII) proliferation model assuming a linear hierarchy of BASCs, AECII, and AECI cells to achieve lung regrowth.
哺乳动物的器官再生被认为需要一个功能性的干细胞或祖细胞库，但这些细胞在肺再生中的作用尚不清楚。虽然肺泡组织的出生后再生已归因于II型肺泡上皮细胞（AECII），但我们推测支气管肺泡干细胞（BASC）可能在这一过程中发挥重要作用。为了验证这一假设，对成年雌性C57/BL6小鼠进行单侧肺切除术（PNX）以刺激代偿性肺再生。在手术后第1、3、7、14、28和45天记录BASC和AECII的密度，以及形态学和生理学测量结果。PNX术后第7天肺活量恢复。BASC数量在术后第3天增加，到第14天达到对照组的220%（P<0.05），然后在肺再生活跃期结束后恢复到基线水平，而AECII细胞密度增加到基线的124%（无显著性差异）。增殖研究显示，PNX术后前7天BASC和AECII中有显著的BrdU摄取。使用系统生物学模型进行定量分析，以评估BASC和AECII的潜在贡献。该模型表明，BASC的增殖和分化对代偿性肺泡上皮（I型和II型细胞）再生的贡献在0%至25%之间，表明再生需要AECII的大量贡献。假设BASC、AECII和AECI细胞呈线性层级关系，使用双室（BASC和AECII）增殖模型可以解释观察到的细胞动力学特征，以实现肺再生。
