PTEN Regulates Myofibroblast Activation in Valvular Interstitial Cells based on Subcellular Localization.

Aortic valve stenosis (AVS) is characterized by altered mechanics of the valve leaflets, which disrupts blood flow through the aorta and can cause left ventricle hypotrophy. These changes in the valve tissue result in activation of resident valvular interstitial cells (VICs) into myofibroblasts, which have increased levels of αSMA in their stress fibers. The persistence of VIC myofibroblast activation is a hallmark of AVS.

Injectable shear-thinning hydrogels promote oligodendrocyte progenitor cell survival and remyelination in the central nervous system.

Cell therapy for the treatment of demyelinating diseases such as multiple sclerosis is hampered by poor survival of donor oligodendrocyte cell preparations, resulting in limited therapeutic outcomes. Excessive cell death leads to the release of intracellular alloantigens, which likely exacerbate local inflammation and may predispose the graft to eventual rejection. Here, we engineered innovative cell-instructive shear-thinning hydrogels (STHs) with tunable viscoelasticity and bioactivity for minimally invasive delivery of primary human oligodendrocyte progenitor cells (hOPCs) to the brain of a mouse, a model of congenital hypomyelinating disease.

Immobilized NRG1 Accelerates Neural Crest like Cell Differentiation Toward Functional Schwann Cells Through Sustained Erk1/2 Activation and YAP/TAZ Nuclear Translocation.

Neural Crest cells (NC) are a multipotent cell population that give rise to a multitude of cell types including Schwann cells (SC) in the peripheral nervous system (PNS). Immature SC interact with neuronal axons via the neuregulin 1 (NRG1) ligand present on the neuronal surface and ultimately form the myelin sheath. Multiple attempts to derive functional SC from pluripotent stem cells have met challenges with respect to expression of mature markers and axonal sorting.

Wnt/BMP Mediated Metabolic Reprogramming Preserves Multipotency of Neural Crest-Like Stem Cells.

Neural crest-like stem cells resembling embryonic neural crest cells (NCs) can be derived from adult human tissues such as the epidermis. However, these cells lose their multipotency rapidly in culture limiting their expansion for clinical use. Here, we show that the multipotency of keratinocyte-derived NCs (KC-NCs) can be preserved by activating the Wnt and BMP signaling axis, promoting expression of key NC-specifier genes and ultimately enhancing their differentiation potential.

Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells.

Mitochondrial dysfunction, a hallmark of aging, has been associated with the onset of aging phenotypes and age-related diseases. Here, we report that impaired mitochondrial function is associated with increased glutamine catabolism in senescent human mesenchymal stem cells (MSCs) and myofibroblasts derived from patients suffering from Hutchinson-Gilford progeria syndrome. Increased glutaminase (GLS1) activity accompanied by loss of urea transporter SLC14A1 induces urea accumulation, mitochondrial dysfunction, and DNA damage.

Engineering Nanofiber Scaffolds with Biomimetic Cues for Differentiation of Skin-Derived Neural Crest-like Stem Cells to Schwann Cells.

Our laboratory reported the derivation of neural crest stem cell (NCSC)-like cells from the interfollicular epidermis of the neonatal and adult epidermis. These keratinocyte (KC)-derived Neural Crest (NC)-like cells (KC-NC) could differentiate into functional neurons, Schwann cells (SC), melanocytes, and smooth muscle cells in vitro. Most notably, KC-NC migrated along stereotypical pathways and gave rise to multiple NC derivatives upon transplantation into chicken embryos, corroborating their NC phenotype.

Adult tissue-derived neural crest-like stem cells: Sources, regulatory networks, and translational potential.

Neural crest (NC) cells are a multipotent stem cell population that give rise to a diverse array of cell types in the body, including peripheral neurons, Schwann cells (SC), craniofacial cartilage and bone, smooth muscle cells, and melanocytes. NC formation and differentiation into specific lineages takes place in response to a set of highly regulated signaling and transcriptional events within the neural plate border. Premigratory NC cells initially are contained within the dorsal neural tube from which they subsequently emigrate, migrating to often distant sites in the periphery.

Restoring extracellular matrix synthesis in senescent stem cells.

Collagen type III (COL3) is one of the 3 major collagens in the body, and loss of expression or mutations in the gene have been associated with the onset of vascular diseases such the Ehlers-Danlos syndrome. Previous work reported a significant reduction of COL3 in tissues such as skin and vessels with aging. In agreement, we found that COL3 was significantly reduced in senescent human mesenchymal stem cells and myofibroblasts derived from patients with Hutchinson-Gilford progeria syndrome, a premature aging syndrome.

Neural crest stem cells from human epidermis of aged donors maintain their multipotency in vitro and in vivo.

Neural crest (NC) cells are multipotent stem cells that arise from the embryonic ectoderm, delaminate from the neural tube in early vertebrate development and migrate throughout the developing embryo, where they differentiate into various cell lineages. Here we show that multipotent and functional NC cells can be derived by induction with a growth factor cocktail containing FGF2 and IGF1 from cultures of human inter-follicular keratinocytes (KC) isolated from elderly donors. Adult NC cells exhibited longer doubling times as compared to neonatal NC cells, but showed limited signs of cellular senescence despite the advanced age of the donors and exhibited significantly younger epigenetic age as compared to KC.

Derivation of neural crest stem cells from human epidermal keratinocytes requires FGF-2, IGF-1, and inhibition of TGF-β1.

Neural crest (NC) cells play a central role in forming the peripheral nervous system, the craniofacial skeleton, and the pigmentation of the skin during development due to their broad multilineage differentiation potential into neurons, Schwann cells, melanocytes, and mesenchymal stem cells. Recently, we identified an easily accessible source of pluripotent NC stem cells from human inter-follicular keratinocyte (KC) cultures (KC-NC). In this work, we examined specific conditions for the derivation of NC from KC cultures.

Reprogramming Postnatal Human Epidermal Keratinocytes Toward Functional Neural Crest Fates.

During development, neural crest (NC) cells are induced by signaling events at the neural plate border of all vertebrate embryos. Initially arising within the central nervous system, NC cells subsequently undergo an epithelial to mesenchymal transition to migrate into the periphery, where they differentiate into diverse cell types. Here we provide evidence that postnatal human epidermal keratinocytes (KC), in response to fibroblast growth factor 2 and insulin like growth factor 1 signals, can be reprogrammed toward a NC fate.