Human Developmental Chondrogenesis as a Basis for Engineering Chondrocytes from Pluripotent Stem Cells

Abstract

SummaryJoint injury and osteoarthritis affect millions of people worldwide, but attempts to generate articular cartilage using adult stem/progenitor cells have been unsuccessful. We hypothesized that recapitulation of the human developmental chondrogenic program using pluripotent stem cells (PSCs) may represent a superior approach for cartilage restoration. Using laser-capture microdissection followed by microarray analysis, we first defined a surface phenotype (CD166low/negCD146low/negCD73+CD44lowBMPR1B+) distinguishing the earliest cartilage committed cells (prechondrocytes) at 5–6 weeks of development. Functional studies confirmed these cells are chondrocyte progenitors. From 12 weeks, only the superficial layers of articular cartilage were enriched in cells with this progenitor phenotype. Isolation of cells with a similar immunophenotype from differentiating human PSCs revealed a population of CD166low/negBMPR1B+ putative cartilage-committed progenitors. Taken as a whole, these data define a developmental approach for the generation of highly purified functional human chondrocytes from PSCs that could enable substantial progress in cartilage tissue engineering.

Kappa opioid receptor signaling protects cartilage tissue against posttraumatic degeneration

“…In our previous study, high expression of the Oprk1 gene encoding KOR was shown in developing human limbs (17). However, no skeletal phenotype was found in Oprk1 -/-mice (19).…”

“…We have previously reported a number of genes that are enriched in human cartilage-committed mesenchymal cells (prechondrocytes) by microarray analysis when comparing prechondrocytes with total limb cells (17). The gene encoding KOR, Oprk1, showed the highest enrichment relative to other genes.…”

“…reported in cartilage (17), although the function of KOR signaling in cartilage development and cartilage matrix homeostasis is largely unknown.…”

Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair

“…To identify compounds that could inhibit hypertrophy, we isolated total limb cells from Col10a1 -mCherry mice27 and cultured them in the presence of bone morphogenetic protein (BMP)-4, a driver of developmental chondrocyte hypertrophy;28 170 000 compounds were assayed for their ability to decrease the mCherry signal (figure 1A). Seventy-five were chosen for follow-up (figure 1B), and additional vetting based on reproducibility and magnitude of Col10a1 inhibition led to the selection of regulator of cartilage growth and differentiation (RCGD) 423 for continued characterisation (figure 1C).…”

Terapias Celulares y Productos de Ingeniería de Tejidos para el Tratamiento de Lesiones Condrales de Rodilla

“…La organización microestructural de estos componentes confiere al cartílago sus propiedades anatómicas y funcionales, siendo el colágeno tipo II y el agrecano las moléculas más abundantes e importantes del cartílago hialino articular (Maroudas et al, 1998). Cuando el cartí-lago hialino se daña es reemplazado por fibrocartílago, el cual contiene colágeno tipos I y II y posee características morfológicas y funcionales diferentes (Wu et al, 2013).…”