The therapeutic application of human induced pluripotent stem cells (hiPSCs) for cartilage regeneration is largely hindered by the low yield of chondrocytes accompanied by unpredictable and heterogeneous off-target differentiation of cells during chondrogenesis. Here, we combine bulk RNA sequencing, single cell RNA sequencing, and bioinformatic analyses, including weighted gene co-expression analysis (WGCNA), to investigate the gene regulatory networks regulating hiPSC differentiation under chondrogenic conditions. We identify specific WNTs and MITF as hub genes governing the generation of off-target differentiation into neural cells and melanocytes during hiPSC chondrogenesis. With heterocellular signaling models, we further show that WNT signaling produced by off-target cells is responsible for inducing chondrocyte hypertrophy. By targeting WNTs and MITF, we eliminate these cell lineages, significantly enhancing the yield and homogeneity of hiPSC-derived chondrocytes. Collectively, our findings identify the trajectories and molecular mechanisms governing cell fate decision in hiPSC chondrogenesis, as well as dynamic transcriptome profiles orchestrating chondrocyte proliferation and differentiation.

Background The decision to perform endoscopic versus the mini-open carpal tunnel release technique is most likely left to surgeons rather than patients with idiopathic carpal tunnel syndrome. Questions/purposes We hypothesized that (1) at 3 months after surgery, the subjective outcomes of endoscopic release, performed on one hand, and mini-incision release, performed on the other, would not differ in patients with bilateral carpal tunnel syndrome; however, (2) each patient would likely prefer one technique over the other for specific reasons. Methods Fifty-two patients with bilateral carpal tunnel syndrome had one hand randomized to undergo endoscopic release and the other to undergo mini-incision release. Each patient was assessed with the Boston Carpal Tunnel Questionnaire (BCTQ) and DASH preoperatively and at each followup. Three months after surgery, the patients commented on which technique they preferred and completed a questionnaire regarding the reasons for not preferring the other technique. Results The mean BCTQ symptom/function score and DASH improved similarly in the endoscopic release group and the mini-incision release group. Thirty-four patients preferred endoscopic release and 13 preferred the miniincision technique. Scar or pillar pain was the most commonly cited factor in not preferring either technique followed by postoperative pain for the open technique and transient worsening of symptoms for the endoscopic technique. Conclusions Despite similar improvements in BCTQ and DASH scores after endoscopic and open techniques at 3 months postoperatively, the majority of our patients preferred the endoscopic technique. The most concerning reason for not preferring the other technique was scar or pillar pain. Level of Evidence Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Osteoarthritis (OA), the leading cause of pain and disability worldwide, disproportionally affects individuals with obesity. The mechanisms by which obesity leads to the onset and progression of OA are unclear due to the complex interactions among the metabolic, biomechanical, and inflammatory factors that accompany increased adiposity. We used a murine preclinical model of lipodystrophy (LD) to examine the direct contribution of adipose tissue to OA. Knee joints of LD mice were protected from spontaneous or posttraumatic OA, on either a chow or high-fat diet, despite similar body weight and the presence of systemic inflammation. These findings indicate that adipose tissue itself plays a critical role in the pathophysiology of OA. Susceptibility to posttraumatic OA was reintroduced into LD mice using implantation of a small adipose tissue depot derived from wild-type animals or mouse embryonic fibroblasts that undergo spontaneous adipogenesis, implicating paracrine signaling from fat, rather than body weight, as a mediator of joint degeneration.