Type II Collagen-Positive Embryonic Progenitors are the Major Contributors to Spine and Intervertebral Disc Development and Repair

Abstract

Basic mechanism of spine development is poorly understood. Type II collagen positive (Col2+) cells have been reported to encompass early mesenchymal progenitors that continue to become chondrocytes, osteoblasts, stromal cells, and adipocytes in long bone. However, the function of Col2+ cells in spine and intervertebral disc (IVD) development is largely unknown. To further elucidate the function of Col2+ progenitors in spine, we generated the mice with ablation of Col2+ cells either at embryonic or at postnatal stage. Embryonic ablation of Col2+ progenitors caused the mouse die at newborn with the absence of all spine and IVD. Moreover, postnatal deletion Col2+ cells in spine resulted in a shorter growth plate and endplate cartilage, defected inner annulus fibrosus, a less compact and markedly decreased gel‐like matrix in the nucleus pulposus and disorganized cell alignment in each compartment of IVD. Genetic lineage tracing IVD cell populations by using inducible Col2‐creERT;tdTomato reporter mice and non‐inducible Col2‐cre;tdTomato reporter mice revealed that the numbers and differentiation ability of Col2+ progenitors decreased with age. Moreover, immunofluorescence staining showed type II collagen expression changed from extracellular matrix to cytoplasm in nucleus pulposus between 6 month and 1‐year‐old mice. Finally, fate‐mapping studies revealed that Col2+ progenitors are essential for IVD repair in IVD injured model. In summary, embryonic Col2+ cells are the major source of spine development and Col2+ progenitors are the important contributors for IVD repair and regeneration.

Constitutive and conditional gene knockout mice for the study of intervertebral disc degeneration: Current status, decision considerations, and future possibilities

“…Green fluorescent protein (GFP) expression was detected in NP, AF, CEP, and GP of lumbar spine. 79 , 90 , 91 And the researchers found similar GFP expression levels in the discs of 2‐week‐old and 2‐month‐old mice. Thus, Col2 Cre recombinase is widely activated in IVD (Table 3 ).…”

“…Typically, Col2 Cre consists of a 3 kb Col2a1 promoter, a 3.02 kb GP of lumbar spine. 79,90,91 And the researchers found similar GFP expression levels in the discs of 2-week-old and 2-month-old mice.…”

“…Col2 Cre mice were hybridized with Rosa26 (R26)‐mTmG mice, then obtaining IVDs of offspring Col2 Cre;R26‐mTmG mice at 2 weeks and 2 months of age. Green fluorescent protein (GFP) expression was detected in NP, AF, CEP, and GP of lumbar spine 79,90,91 . And the researchers found similar GFP expression levels in the discs of 2‐week‐old and 2‐month‐old mice.…”

Trp53 controls chondrogenesis and endochondral ossification by negative regulation of TAZ activity and stability via β-TrCP-mediated ubiquitination

“…However, our results showed that Trp53 expression is gradually decreased during chondrogenesis. Another reason is that Col2-positive cells are decreased with age [ 41 ]. While accumulating evidence suggested that aging was a major risk factor of tumorigenesis that displayed an inevitable time-dependent manner [ 42 , 43 ].…”

Nutritional deficiency induces nucleus pulposus cell apoptosis via the ATF4-PKM2-AKT signal axis

“…The IVD is composed of the central nucleus pulposus (NP), the surrounding annulus fibrosus (AF) ring, and cartilaginous endplates. Nucleus pulposus cells (NPCs) are the major cells that reside in the NP and are important for the preservation of the extracellular matrix (ECM), such as aggrecan and type II collagen (Col2α1), and thus maintain the normal physiological function of IVDs [11][12][13]. Although the exact etiology of IVDD remains unclear, significantly increased NPC apoptosis and reduced cell proliferation are proven to be important contributors to IVDD [11,14,15].…”