Laboratory of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, 400042, China.
Department of Rehabilitation Medicine, General Hospital of Central Theater Command of Chinese People's Liberation Army, Wuhan, China.
Stem Cell Res Ther. 2022 Jun 3;13(1):227. doi: 10.1186/s13287-022-02903-2.
Intervertebral disc degeneration (IVDD) can cause low back pain, a major public health concern. IVDD is characterized with loss of cells especially those in nucleus pulposus (NP), due to the limited proliferative potential and regenerative ability. Few studies, however, have been carried out to investigate the in vivo proliferation events of NP cells and the cellular contribution of a specific subpopulation of NP during postnatal growth or regeneration.
We generated FGFR3-3*Flag-IRES-GFP mice and crossed FGFR3-CreERT2 mice with Rosa26-mTmG, Rosa26-DTA and Rosa26-Confetti mice, respectively, to perform inducible genetic tracing studies.
Expression of FGFR3 was found in the outer region of NP with co-localized expressions of proliferating markers. By fate mapping studies, FGFR3-positive (FGFR3) NP cells were found proliferate from outer region to inner region of NP during postnatal growth. Clonal lineage tracing by Confetti mice and ablation of FGFR3 NP cells by DTA mice further revealed that the expansion of the FGFR3 cells was required for the morphogenesis and homeostasis of postnatal NP. Moreover, in degeneration and regeneration model of mouse intervertebral disc, FGFR3 NP cells underwent extensive expansion during the recovery stage.
Our present work demonstrates that FGFR3 NP cells are novel subpopulation of postnatal NP with long-existing proliferative capacity shaping the adult NP structure and participating in the homeostasis maintenance and intrinsic repair of NP. These findings may facilitate the development of new therapeutic approaches for IVD regeneration.
椎间盘退变（IVDD）可导致腰痛，这是一个主要的公共健康问题。IVDD的特征是细胞，尤其是髓核（NP）中的细胞丢失，这是由于 NP 细胞的增殖潜力有限和再生能力有限。然而，很少有研究调查 NP 细胞的体内增殖事件以及 NP 在出生后生长或再生过程中特定亚群的细胞贡献。
我们生成了 FGFR3-3*Flag-IRES-GFP 小鼠，并分别将 FGFR3-CreERT2 小鼠与 Rosa26-mTmG、Rosa26-DTA 和 Rosa26-Confetti 小鼠杂交，以进行诱导遗传追踪研究。
发现 FGFR3 在 NP 的外区表达，并与增殖标记物共表达。通过命运图谱研究，发现 FGFR3 阳性（FGFR3）NP 细胞在出生后生长过程中从 NP 的外区向内区增殖。通过 Confetti 小鼠进行克隆谱系追踪和通过 DTA 小鼠清除 FGFR3 NP 细胞进一步表明，FGFR3 细胞的扩增对于 NP 的形态发生和出生后 NP 的稳态是必需的。此外，在小鼠椎间盘退变和再生模型中，FGFR3 NP 细胞在恢复阶段经历了广泛的扩增。
本研究表明，FGFR3 NP 细胞是 NP 中具有长期存在的增殖能力的新型亚群，其形成成年 NP 结构，并参与 NP 的稳态维持和内在修复。这些发现可能有助于开发新的椎间盘再生治疗方法。
