Direct Induction of Chondrogenic Cells from Human Dermal Fibroblast Culture by Defined Factors

Abstract

The repair of large cartilage defects with hyaline cartilage continues to be a challenging clinical issue. We recently reported that the forced expression of two reprogramming factors (c-Myc and Klf4) and one chondrogenic factor (SOX9) can induce chondrogenic cells from mouse dermal fibroblast culture without going through a pluripotent state. We here generated induced chondrogenic (iChon) cells from human dermal fibroblast (HDF) culture with the same factors. We developed a chondrocyte-specific COL11A2 promoter/enhancer lentiviral reporter vector to select iChon cells. The human iChon cells expressed marker genes for chondrocytes but not fibroblasts, and were derived from non-chondrogenic COL11A2-negative cells. The human iChon cells formed cartilage but not tumors in nude mice. This approach could lead to the preparation of cartilage directly from skin in human, without going through pluripotent stem cells.

AP-1 family members act with Sox9 to promote chondrocyte hypertrophy

“…Moreover, Sox9 is sufficient to initiate chondrogenic programs when activated in mesenchymal stem cells (Ikeda et al, 2004), embryonic stem cells (Ikeda et al, 2004) and human dermal fibroblasts (Ikeda et al, 2004;Ohba et al, 2015;Outani et al, 2013). Inactivating mutations in human SOX9 result in campomelic dysplasia, an autosomal dominant disorder characterized by hypoplasia of the endochondral skeleton and bowing of skeletal elements (Foster, 1996;Giordano et al, 2001;Kwok et al, 1995).…”

Gene Modification of Mesenchymal Stem Cells and Articular Chondrocytes to Enhance Chondrogenesis

“…Of these transcription factors, the overexpression of Klf4 and c-Myc with Sox9 yielded the highest efficiency in chondrogenic differentiation resulting in extracellular matrix secretion, with physical and histological properties as those of articular cartilage. This result has also been shown in the direct differentiation of human dermal fibroblasts to chondrocytes with the same factors [63]. The codelivery of one or more chondrogenic factors along with potential repressors of hypertrophy or dedifferentiation may promote the maintenance of the chondrogenic phenotype.…”

From Skeletal Development to Tissue Engineering: Lessons from the Micromass Assay

“…For example, chondrocytes were transdifferentiated directly from somatic cells using a combination of reprogramming and chondrogenic factors. [111][112][113] Such approaches have great potential but should be well characterized and regulated to diminish the risk of teratoma formation and immune rejection.…”