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. Application of human induced pluripotent stem cells (hiPSCs) for tissue regeneration is hindered by off-target cell differentiation. Here, the authors use bulk and single cell RNA-sequencing to identify WNT and MITF as off-target hubs during chondrogenic differentiation; inhibiting these pathways enhanced homogeneity and yield.

/pdf/single-cell-transcriptomic-analysis-of-human-pluripotent-iz6qpmloua.pdf

Single cell transcriptomic analysis of human pluripotent stem cell chondrogenesis.

https://eprints.ncl.ac.uk/file_store/production/274072/74C2E394-10D4-470E-BBEE-7BBB5D5F5EF8.pdf

Genetics of osteoarthritis.

The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltage-gated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases. This article is categorized under: Cardiovascular Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology Congenital Diseases > Stem Cells and Development Cancer > Stem Cells and Development.

New developments in the biology of fibroblast growth factors.

Genetics of osteoarthritis

Transient receptor potential vanilloid 4 (TRPV4) is a polymodal calcium-permeable cation channel that is highly expressed in cartilage and is sensitive to a variety of extracellular stimuli. The expression of this channel has been associated with the process of chondrogenesis in adult stem cells as well as several cell lines. Here, we used a chondrogenic reporter (Col2a1-GFP) in murine induced pluripotent stem cells (iPSCs) to examine the hypothesis that TRPV4 serves as both a marker and a regulator of chondrogenesis. Over 21 days of chondrogenesis, iPSCs showed significant increases in Trpv4 expression along with the standard chondrogenic gene markers Sox9, Acan, and Col2a1, particularly in the green fluorescent protein positive (GFP+) chondroprogenitor subpopulation. Increased gene expression for Trpv4 was also reflected by the presence of TRPV4 protein and functional Ca2+ signaling. Daily activation of TRPV4 using the specific agonist GSK1016790A resulted in significant increases in cartilaginous matrix production. An improved understanding of the role of TRPV4 in chondrogenesis may provide new insights into the development of new therapeutic approaches for diseases of cartilage, such as osteoarthritis, or channelopathies and hereditary disorders that affect cartilage during development. Harnessing the role of TRPV4 in chondrogenesis may also provide a novel approach for accelerating stem cell differentiation in functional tissue engineering of cartilage replacements for joint repair.

Transient receptor potential vanilloid 4 as a regulator of induced pluripotent stem cell chondrogenesis

Humans have limited regenerative potential of musculoskeletal tissues following limb or digit loss. The murine digit has been used to study mammalian regeneration, where stem/progenitor cells (the ‘blastema’) regrow the digit tip after distal, but not proximal, amputation. However, the molecular mechanisms responsible for this response remain to be determined. We hypothesized that regeneration is initiated and maintained by a gene regulatory network that recapitulates aspects of limb development, whereas a non-regenerative response exhibits fibrotic wound healing and minimal bone remodeling. To test these hypotheses, we evaluated the spatiotemporal formation of bone and fibrous tissues after level-dependent amputation of the murine terminal phalanx and quantified the transcriptome of the repair tissue. We show that digit regeneration is a level-dependent and spatiotemporally controlled process, with distal and proximal amputations showing significant differences in gene expression and tissue regrowth over time. Regeneration is characterized by the transient upregulation of genes that direct skeletal system development and limb morphogenesis, including distal Hox genes. By identifying the molecular pathways regulating regeneration, this work will lead to novel therapies that restore complex tissues after injury. Summary Statement Murine digit tip regeneration after distal amputation is orchestrated through a transient, limb-specific gene network by blastema cells. Proximal amputation activates an alternate transcriptional program that results in scar formation.

https://www.biorxiv.org/content/biorxiv/early/2019/05/20/643361.full.pdf

Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse

Humans have limited regenerative potential of musculoskeletal tissues following limb or digit loss. The murine digit has been used to study mammalian regeneration, where stem/progenitor cells (the "blastema") completely regenerate the digit tip after distal, but not proximal, amputation. However, the molecular mechanisms responsible for this response remain to be determined. Here, we evaluated the spatiotemporal formation of bone and fibrous tissues after level-dependent amputation of the murine terminal phalanx and quantified the transcriptome of the repair tissue. Distal (regenerative) and proximal (non-regenerative) amputations showed significant differences in temporal gene expression and tissue regrowth over time. Genes that direct skeletal system development and limb morphogenesis are transiently upregulated during blastema formation and differentiation, including distal Hox genes. Overall, our results suggest that digit tip regeneration is controlled by a gene regulatory network that recapitulates aspects of limb development, and that failure to activate this developmental program results in fibrotic wound healing.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.202000330R

Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse.

An immortalized human adipose-derived stem cell line with highly enhanced chondrogenic properties.

Background Retronasal olfaction (RNO) refers to the perception of odorants inhaled through the mouth and carried through the nasopharynx to olfactory receptors within the olfactory cleft, enabling the perception of flavor. Although orthonasal olfactory dysfunction in chronic rhinosinusitis (CRS) has been widely described, the impact of CRS on RNO is less clear. In this study, we systematically review available literature to provide an update on RNO in the setting of CRS. Methods We systematically searched PubMed, Ovid Embase, Web of Science, and the Cochrane Library for studies examining RNO in patients with documented CRS. The primary outcome of interest was objective psychophysical measurement of olfaction, including characterization of RNO. Results We identified 404 unique references that underwent title and abstract review by two independent reviewers, with 52 articles undergoing full-text review, where 10 relevant studies underwent data extraction. Although outcome measures varied, all included studies demonstrated diminished RNO in patients with CRS. Of six studies evaluating the relationship between retronasal and orthonasal olfactory test scores in CRS patients two out of six (33%) demonstrated a correlation between both forms of olfaction and CRS, and two out of six studies (33%) found significantly lower orthonasal olfactory test scores compared to retronasal olfactory test scores. Two of three found significant improvement in RNO with treatment of underlying CRS. Of three studies examining patient reported outcome measures (PROMs) in CRS, two found significant associations between retronasal olfactory test scores and PROMs. Conclusions Based on the current literature, CRS patients appear to have diminished RNO, which may be associated with orthonasal olfactory dysfunction and decreased quality of life in this population. Higher level of evidence studies are required to further elucidate these relationships and the impact of medical and surgical CRS management on RNO.

Beyond aroma: A scoping review on the impact of chronic rhinosinusitis on retronasal olfaction

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Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse

Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse.

An immortalized human adipose-derived stem cell line with highly enhanced chondrogenic properties.

Beyond aroma: A scoping review on the impact of chronic rhinosinusitis on retronasal olfaction