Dynamics of Transcription Factors in Three Early Phases of Osteogenic, Adipogenic, and Chondrogenic Differentiation Determining the Fate of Bone Marrow Mesenchymal Stem Cells in Rats

Abstract

The imbalance of osteogenic, adipogenic, and chondrogenic differentiation in bone marrow mesenchymal stem cells (BMSCs) occurred in multiple age-related degenerative diseases such as osteoporosis and osteoarthritis. In order to improve our understanding and control of multi-directional differentiation of BMSCs in rats, using high-throughput sequencing, we identified key gene regulatory events in the early stages of lineage commitment. Data analysis revealed two transcription factors (TFs, Tsc22d3, and Epas1) with elevated expression throughout the initiation of differentiation (3 h), lineage acquisition (12 h), and early lineage progression (72 h) of three-directional differentiation. For osteogenic differentiation, 792, 1,042, and 638 differentially expressed genes including 48, 59, and 34 TFs were identified at three time points, respectively. Moreover, the functional analysis demonstrated that 4, 12, and 5 TFs were only differentially expressed during osteogenic differentiation at 3, 12, and 72 h, respectively, and not during other two-directional differentiation. Hopx showed enhanced expression throughout three early phases during the osteogenic differentiation but no significant change in other two-directional differentiation. A similar pattern of Gbx2 expression occurred in chondrogenic differentiation. Thus, Hopx and other early responder TFs may control the osteogenic cell fate of BMSCs and participate in the development of osteoporosis. Gbx2 and other early responder TFs should be considered in mechanistic models that clarify cartilage-anabolic changes in the clinical progression of osteoarthritis.

Osteoimmune Interactions and Therapeutic Potential of Macrophage-Derived Small Extracellular Vesicles in Bone-Related Diseases

“…When people are experience estrogen deficiency, aging, high levels of glucocorticoids, inflammation and hyperparathyroidism, the balance between the activities of boneforming osteoblasts and bone-resorbing osteoclasts is disrupted, causing the occurrence of osteoporosis. 14,[50][51][52] Osteoporosis is more common in women than in men, and is a strong risk factor for fragility fractures in untreated people. It is estimated that 40% of postmenopausal women and 30% of older men (over 70 years of age) are at risk of experiencing osteoporotic fractures and the number continues to increase, posing tremendous medical and economic challenges to patients and society.…”

Transcriptome Sequencing Reveals Key Genes in Three Early Phases of Osteogenic, Adipogenic, and Chondrogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in Rats

“…The RNA quality assessment, mRNA library construction, and mRNA sequencing were performed using methods described in the previous study (Zhang et al, 2021). Based on the annotation information in the platform, the probe sets were transformed into the corresponding gene symbol.…”

N6-Methyladenosine in Cell-Fate Determination of BMSCs: From Mechanism to Applications

“…Bone has a self-repair ability so that it can renew itself when the nature and extent of the defect are not large, severe, and chronic [ 1 – 3 ]. The reparative process of bone is initiated by bone mesenchymal stem cells (BMSCs) residing in the bone marrow, which are multipotent stem cells with the ability to differentiate into various cell types, including osteoblasts, adipocytes, chondrocytes, and fibroblasts [ 1 , 2 , 4 ]. Data analysis revealed two distinct phases of the BMSC differentiation process, namely, lineage commitment (from MSCs to lineage-specific progenitors) and maturation (from progenitors to specific cell types) [ 2 ].…”

“…The reparative process of bone is initiated by bone mesenchymal stem cells (BMSCs) residing in the bone marrow, which are multipotent stem cells with the ability to differentiate into various cell types, including osteoblasts, adipocytes, chondrocytes, and fibroblasts [ 1 , 2 , 4 ]. Data analysis revealed two distinct phases of the BMSC differentiation process, namely, lineage commitment (from MSCs to lineage-specific progenitors) and maturation (from progenitors to specific cell types) [ 2 ]. The dysregulation of adipose-osteogenic balance could result in the formation of excessive fat and compromised bone structure, contributing to the pathogenesis of multiple musculoskeletal conditions [ 5 , 6 ].…”

“…The dysregulation of adipose-osteogenic balance could result in the formation of excessive fat and compromised bone structure, contributing to the pathogenesis of multiple musculoskeletal conditions [ 5 , 6 ]. The differentiation of BMSCs is regulated by the activation of specific intracellular transcription factors (TFs), signaling pathways, and noncoding RNAs (ncRNAs; e.g., miRNA, lncRNA, and circRNA) [ 2 , 7 ]. In addition, extracellular elements such as hypoxia and mechanical stimulation are also involved in these vital processes [ 8 ].…”