Search

Members of the phosphodiesterase 4 (PDE4) enzyme family regulate the availability of the secondary messenger cyclic adenosine monophosphate (cAMP) and, by doing so, control cellular processes in health and disease. In particular, PDE4D has been associated with Alzheimer's disease and the intellectual disability seen in fragile X syndrome. Furthermore, single point mutations in critical PDE4D regions cause acrodysostosis type 2(ACRDYS2, also referred to as inactivating PTH/PTHrP signalling disorder 5 or iPPSD5), where intellectual disability is seen in ∼90% of patients alongside the skeletal dysmorphologies that are characteristic of acrodysostosis type 1 (ACRDYS1/iPPSD4) and ACRDYS2. Two contrasting mechanisms have been proposed to explain how mutations in PDE4D cause iPPSD5. The first mechanism, the 'over-activation hypothesis', suggests that cAMP/PKA (cyclic adenosine monophosphate/protein kinase A) signalling is reduced by the overactivity of mutant PDE4D, whilst the second, the 'over-compensation hypothesis' suggests that mutations reduce PDE4D activity. That reduction in activity is proposed to cause an increase in cellular cAMP, triggering the overexpression of other PDE isoforms. The resulting over-compensation then reduces cellular cAMP and the levels of cAMP/PKA signalling. However, neither of these proposed mechanisms accounts for the fine control of PDE activation and localization, which are likely to play a role in the development of iPPSD5. This review will draw together our understanding of the role of PDE4D in iPPSD5 and present a novel perspective on possible mechanisms of disease., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

While human adipose-derived stem cells (hADSCs) are known to possess osteogenic differentiation potential, the bone tissues formed are generally considered rudimentary and immature compared with those made by bone-derived precursor cells such as human bone marrow-derived mesenchymal stem cells (hBMSCs) and less commonly studied human calvarium osteoprogenitor cells (hOPs). Traditional differentiation protocols have tended to focus on osteoinduction of hADSCs through the addition of osteogenic differentiation media or use of stimulatory bioactive scaffolds which have not resulted in mature bone formation. Here, we tested the hypothesis that by reproducing the physical as well as biochemical bone microenvironment through the use of three-dimensional (3D) culture and vascularization we could enhance osteogenic maturation in hADSCs. In addition to biomolecular characterization, we performed structural analysis through extracellular collagen alignment and mineral density in our bone tissue engineered samples to evaluate osteogenic maturation. We further compared bone formed by hADSCs, hBMSCs, and hOPs against mature human pediatric calvarial bone, yet not extensively investigated. Although bone generated by all three cell types was still less mature than native pediatric bone, a fibrin-based 3D microenvironment together with vascularization boosted osteogenic maturation of hADSC making it similar to that of bone-derived osteoprogenitors. This demonstrates the important role of vascularization and 3D culture in driving osteogenic maturation of cells easily available but constitutively less committed to this lineage and suggests a crucial avenue for recreating the bone microenvironment for tissue engineering of mature craniofacial bone tissues from pediatric hADSCs, as well as hBMSCs and hOPs., (© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Adipose-derived stem cells (ADSC) have come to be viewed as a ubiquitous solution for aesthetic and reconstructive problems involving loss of tissue volume and age or radiation-induced loss of tissue pliability and vascularity. As the theoretical potential of "stem cell therapy" has captured the public imagination, so the commercial potential of novel therapies is being exploited beyond scientifically sound, hypothesis-driven paradigms and in the absence of evidence establishing clinical efficacy and safety. Moreover, with variations in methods of isolation, manipulation, and reintroduction described, it is unclear how the practitioner with an interest in ADSC can harness the clinical potential in reproducible and scientifically measurable ways. This Continuing Medical Education (CME) article presents a summary of our understanding of what ADSC are, their utility within the field of aesthetic surgery, and the current and future directions for adipose stem cell research., (© 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.)

Context: The hormone fibroblast growth factor 21 (FGF21) is a key metabolic regulator in the adaptation to fasting. In food-restricted mice, inhibition of skeletal growth is mediated by the antagonistic effect of FGF21 on GH action in the liver and growth plate., Objective: The objective of the study was to assess the role of FGF21 in growth regulation in humans using postnatal growth failure of very preterm infants as a model., Design: FGF21 levels were measured serially in very preterm infants, and their linear growth evaluated from birth to term-equivalent age. Primary chondrocytes obtained from pediatric donors were used to test whether FGF21 can directly interfere with GH signaling., Results: A negative association (β -.415, P < .005, linear regression model) of FGF21 levels with the change in SD score for length was found. In primary chondrocytes, FGF21 upregulated basal and GH-induced SOCS2 expression and inhibited GH-induced signal transducer and activator of transcription 5 (STAT5) phosphorylation as well as GH-induced COLII and ALP expression. Finally, FGF21 inhibited GH-induced IGF-1 expression and cell proliferation, indicating GH resistance. However, FGF21 did not affect IGF-1-induced cell proliferation., Conclusions: Elevated FGF21 serum levels during the first weeks of life are independently associated with postnatal growth failure in preterm infants. Furthermore, our data provide mechanistic insights into GH resistance secondary to prematurity and may offer an explanation for the growth failure commonly seen in chronic conditions of childhood.

Stem cells derived from adipose tissue are a potentially important source for autologous cell therapy and disease modeling, given fat tissue accessibility and abundance. Critical to developing standard protocols for therapeutic use is a thorough understanding of their potential, and whether this is consistent among individuals, hence, could be generally inferred. Such information is still lacking, particularly in children. To address these issues, we have used different methods to establish stem cells from adipose tissue (adipose-derived stem cells [ADSCs], adipose explant dedifferentiated stem cells [AEDSCs]) from several pediatric patients and investigated their phenotype and differentiation potential using monolayer and micromass cultures. We have also addressed the overlooked issue of selective induction of cartilage differentiation. ADSCs/AEDSCs from different patients showed a remarkably similar behavior. Pluripotency markers were detected in these cells, consistent with ease of reprogramming to induced pluripotent stem cells. Significantly, most ADSCs expressed markers of tissue-specific commitment/differentiation, including skeletogenic and neural markers, while maintaining a proliferative, undifferentiated morphology. Exposure to chondrogenic, osteogenic, adipogenic, or neurogenic conditions resulted in morphological differentiation and tissue-specific marker upregulation. These findings suggest that the ADSC "lineage-mixed" phenotype underlies their significant plasticity, which is much higher than that of chondroblasts we studied in parallel. Finally, whereas selective ADSC osteogenic differentiation was observed, chondrogenic induction always resulted in both cartilage and bone formation when a commercial chondrogenic medium was used; however, chondrogenic induction with a transforming growth factor β1-containing medium selectively resulted in cartilage formation. This clearly indicates that careful simultaneous assessment of bone and cartilage differentiation is essential when bioengineering stem cell-derived cartilage for clinical intervention.