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Nature realizes protein and peptide depots by catalyzing covalent bonds with the extracellular matrix (ECM) of tissues. We are translating this natural blueprint for the sustained delivery of a myostatin-inhibiting peptide (Anti-Myo), resulting in an enzyme depot established from injectable solutions. For that, we fused Anti-Myo to the D-domain of insulin-like growth factor I, a transglutaminase (TG) substrate. TG catalyzed the covalent binding of the D-domain to ECM proteins, such as laminin and fibronectin, on bioengineered ECM and in mice. ECM decorated with Anti-Myo suppressed myostatin activity and pathway activation and reduced the differentiation of preconditioned bone marrow-derived macrophages into osteoclasts in vitro., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Insulin-like growth factor 1 (IGF-1) is a critical fetal anabolic hormone. IGF-1 infusion to the normally growing sheep fetus increases the weight of some organs but does not consistently increase body weight. However, IGF-1 infusion profoundly decreases fetal plasma insulin concentrations, which may limit fetal growth potential. In this study, normally growing late-gestation fetal sheep received an intravenous infusion of either: IGF-1 (IGF), IGF-1 with insulin and dextrose to maintain fetal euinsulinemia and euglycemia (IGF+INS), or vehicle control (CON) for 1 week. The fetus underwent a metabolic study immediately prior to infusion start and after 1 week of the infusion to measure uterine and umbilical uptake rates of nutrients and oxygen. IGF+INS fetuses were 23% heavier than CON (P = 0.0081) and had heavier heart, liver, and adrenal glands than IGF and CON (P < 0.01). By design, final fetal insulin concentrations in IGF were 62% and 65% lower than IGF+INS and CON, respectively. Final glucose concentrations were similar in all groups. IGF+INS had lower final oxygen content than IGF and CON (P < 0.0001) and lower final amino acid concentrations than CON (P = 0.0002). Final umbilical oxygen uptake was higher in IGF+INS compared to IGF and CON (P < 0.05). Final umbilical uptake of several essential amino acids was higher in IGF+INS compared to CON (P < 0.05). In summary, maintaining euinsulinemia and euglycemia during fetal IGF-1 infusion is necessary to maximally support body growth. We speculate that IGF-1 and insulin stimulate placental nutrient transport to support fetal growth.

Background: Reduced insulin-like growth factor-1 (IGF-1) levels may contribute to impaired organ development in preterm infants. Using preterm pigs as a model, we hypothesized that IGF-1 supplementation improves health and gut development during the first three weeks of life., Methods: First, clinical and organ endpoints were compared between artificially-reared, cesarean-delivered preterm pigs and vaginally-delivered, sow-reared term pigs at 5, 9 and 19 days. Next, preterm pigs were treated with recombinant human IGF-1 for 19 days (2.25 mg/kg/day, systemically)., Results: Relative to term pigs, preterm pigs had lower body weight, fat, bone contents, relative weights of liver and spleen and a longer and thinner intestine at 19 days. Preterm birth reduced intestinal villi heights and peptidase activities, but only at 5 and 9 days. In preterm pigs, IGF-1 reduced mortality primarily occurring from gastrointestinal complications and with a tendency towards salvaging smaller pigs. IGF-1 supplementation also increased spleen and kidney weights, small intestine length and maltase to lactase activity, reflecting gut maturation., Conclusion: Preterm birth affects body composition and gut maturation in the first 1-2 weeks, but differences are marginal thereafter. Supplemental IGF-1 may improve gut health in pigs and infants in the first few weeks after preterm birth., Impact: Insulin-like growth factor 1 (IGF-1) supplementation may improve gut health and development in prematurity, but whether the effects are sustained beyond the immediate postnatal period is unclear. In preterm pigs, the prematurity effects on IGF-1 and gut health deficiencies are most pronounced during the first week of life and diminishes thereafter. In preterm pigs, IGF-1 supplementation beyond the first week of life reduced mortality. The present study provides evidence of a sustained effect of IGF-1 supplementation on the gastrointestinal tract after the immediate postnatal period., (© 2023. The Author(s).)

To more closely resemble the structure of natural skin, multi-layered wound dressings have been developed. Herein, a tri-layer wound dressing was prepared containing a polyacrylamide (PAAm)-Aloe vera (Alo) sponge that had been incorporated with insulin-like growth factor-1 (IGF1) to provide a porous absorbent layer, which was able to promote angiogenesis. Alo nanofibers with multi-walled carbon nanotubes (MWCNT) were electrospun into the bottom layer to increase cell behavior, and a small film of stearic acid was put as a top layer to avoid germy penetration. In comparison to bilayer dressing, the tensile strength increased by 17.0 % (from 0.200 ± 0.010 MPa to 0.234 ± 0.022 MPa) and the elastic modulus by 45.6 % (from 0.217 ± 0.003 MPa to 0.316 ± 0.012 MPa) in the presence of Alo nanofibers containing 0.5 wt% of MWCNT at the bottom layer of Trilayer0.5 dressing. The release profile of IGF1, the antibacterial activity and the degradability of different wound dressings were investigated. Trilayer0.5 indicated the highest cell viability, cell adhesion and angiogenic potential among the prepared dressing materials. In-vivo rat model revealed that the Trilayer0.5 dressing treated group had the highest rate of wound closure and wound healing within 10 days compared to other groups., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Hypothesis: We investigated the treatment effect of intratympanic insulin-like growth factor-1 (IGF-1) on severe facial paralysis in guinea pigs., Background: The use of regenerative medicine involving growth factors has been reported in the treatment of peripheral nerve diseases. IGF-1 plays a crucial role in nerve regeneration., Methods: We performed the following procedures on guinea pigs. In the normal group (n = 7), no procedure was performed. In the saline (n = 7) and IGF-1 (n = 7) groups, facial paralysis was induced by freezing of the facial canal. Subsequently, in the saline and IGF-1 groups, a gelatin hydrogel impregnated with 100 μL saline and 400 μg/100 μL IGF-1, respectively, was placed in the facial canal. Facial nerve functions were evaluated using three test batteries: facial movement observation, electrophysiological testing, and histological assessment., Results: At 10 weeks postoperatively, the facial movement scores for the IGF-1 group were improved compared to those in the saline group. The conductive velocity was significantly faster in the IGF-1 group than in the saline group. There was a significant between-group difference in the nerve fiber number and myelin thickness., Conclusion: Intratympanic IGF-1 administration improved facial nerve regeneration. This novel method could provide prompt ambulatory regenerative treatment and reduce the incidence of poor recovery in patients with severe facial paralysis., Competing Interests: The authors have no conflicts of interest directly relevant to the content of this article and no funding or financial relationships to disclose., (Copyright © 2021, Otology & Neurotology, Inc.)

There exists little available information on the mechanisms of lactation regulation until now. In order to explore the underlying mechanism, we injected IGF-I and GH recombinant vectors into the mammary gland, then RNA-seq analysis and nuclear proteomics were used for rapid high-throughput screening of DEGs and DEPs in the two groups linked to lactation regulation. KEGG analysis of 206 DEGs showed that the same 4 of top 10 enrichment pathways (ECM receptor interaction, protein digestion and absorption, focal adhesion and phagosome) involved in 4 co-expressed genes (IDO, BTG1, ITGB6 and keratin 83), the two groups enriched different metabolic pathways yet. Nuclear proteomics analysis showed 75 and 36 DEPs in the IGF-I and GH group respectively; Sixteen common proteins were identified between the IGF-I group and GH group, four of which (ALB, TPT1, CXXC-5 and ACTR2) significantly decreased and three of which (PRP1, PAG-9 and Hsp70) significantly increased. Similarly, DEPs in the two groups were enriched in same one of top 10 enrichment pathways (PI3K-Akt signaling pathway). Protein-protein interaction networks highlighted the contribution of glycosphingolipid biosynthesis, porphyrin and chlorophyll metabolism and the Jak-STAT signaling pathway to lactation regulation of GH and IGFI. GH and IGF-I improve milk yield, which may be linked to important nodal proteins (ALB and ACTB). Our research advances the understanding of the mammary gland transcriptome and nuclear proteomics during GH and IGF-I overexpression. Individual genes, proteins and pathways in this study point towards potential targets for lactation regulation., (Copyright © 2021. Published by Elsevier Ltd.)

Fetal growth restriction (FGR) is associated with decreased insulin secretory capacity and decreased insulin sensitivity in muscle in adulthood. We investigated whether intra-amniotic IGF-I treatment in late gestation mitigated the adverse effects of FGR on the endocrine pancreas and skeletal muscle at 18 mo of age. Singleton-bearing ewes underwent uterine artery embolization between 103 and 107 days of gestational age, followed by 5 once-weekly intra-amniotic injections of 360-µg IGF-I (FGRI) or saline (FGRS) and were compared with an unmanipulated control group (CON). We measured offspring pancreatic endocrine cell mass and pancreatic and skeletal muscle mRNA expression at 18 mo of age ( n = 7-9/sex/group). Total α-cell mass was increased ∼225% in FGRI males versus CON and FGRS males, whereas β-cell mass was not different between groups of either sex. Pancreatic mitochondria-related mRNA expression was increased in FGRS females versus CON ( NRF1 , MTATP6 , UCP2 ), and FGRS males versus CON ( TFAM , NRF1 , UCP2 ) but was largely unchanged in FGRI males versus CON. In skeletal muscle, mitochondria-related mRNA expression was decreased in FGRS females versus CON ( PPARGC1A , TFAM, NRF1 , UCP2 , MTATP6 ), FGRS males versus CON ( NRF1 and UCP2 ), and FGRI females versus CON ( TFAM and UCP2 ), with only MTATP6 expression decreased in FGRI males versus CON. Although the window during which IGF-I treatment was delivered was limited to the final 5 wk of gestation, IGF-I therapy of FGR altered the endocrine pancreas and skeletal muscle in a sex-specific manner in young adulthood. NEW & NOTEWORTHY Fetal growth restriction (FGR) is associated with compromised metabolic function throughout adulthood. Here, we explored the long-term effects of fetal IGF-I therapy on the adult pancreas and skeletal muscle. This is the first study demonstrating that IGF-I therapy of FGR has sex-specific long-term effects at both the tissue and molecular level on metabolically active tissues in adult sheep.

This study was designed to examine the effects of seminal insulin-like growth factor-1 (IGF-1) supplementation on structural and functional properties of buffalo sperm post cryopreservation. Semen ejaculates from buffalo bulls (n = 6) were proportioned into four aliquots and diluted with egg yolk-based extender. Prior to equilibration, IGF-1 was added to extender as four treatments: group IGF0 (no supplementation), IGF150 (150 ng/mL), IGF250 (250 ng/mL) and IGF350 (350 ng/mL). The extended semen was transferred into 0.25 mL mini-straws, equilibrated (4 °C at 4 h), and cryopreserved. Total sperm motility was greater (P < 0.05) when there was the IGF150 treatment compared with values for other groups. Furthermore, with the IGF150 treatment there was the least and greatest (P < 0.05) mitochondrial superoxide status and membrane potential, respectively. Similarly, with the IGF150 treatment there was a greater (P < 0.05) sperm membrane integrity with a lesser (P < 0.05) calcium status compared to values for the other groups. In conclusion, seminal IGF-1 supplementation affects the structural and functional properties of buffalo sperm following cryopreservation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The insulin-like growth factor 1 receptor (IGF-1R) signaling in cardiomyocytes is implicated in physiological hypertrophy and myocardial aging. Although fibroblasts account for a small amount of the heart, they are activated when the heart is damaged to promote cardiac remodeling. However, the role of IGF-1R signaling in cardiac fibroblasts is still unknown. In this study, we investigated the roles of IGF-1 signaling during agonist-induced cardiac fibrosis and evaluated the molecular mechanisms in cultured cardiac fibroblasts. Using an experimental model of cardiac fibrosis with angiotensin II/phenylephrine (AngII/PE) infusion, we found severe interstitial fibrosis in the AngII/PE infused myofibroblast-specific IGF-1R knockout mice compared to the wild-type mice. In contrast, low-dose IGF-1 infusion markedly attenuated AngII-induced cardiac fibrosis by inhibiting fibroblast proliferation and differentiation. Mechanistically, we demonstrated that IGF-1-attenuated AngII-induced cardiac fibrosis through the Akt pathway and through suppression of rho-associated coiled-coil containing kinases (ROCK)2-mediated α-smooth muscle actin (αSMA) expression. Our study highlights a novel function of the IGF-1/IGF-1R signaling in agonist-induced cardiac fibrosis. We propose that low-dose IGF-1 may be an efficacious therapeutic avenue against cardiac fibrosis., (© 2021. The Author(s).)

Insulin-like growth factor-I (IGF-I) and its analogs LongR 3 -IGF-I, Des(1-3)-IGF-I, and R 3 -IGF-I are prohibited substances in sport. Although they were never approved for use in humans, they are readily available as black market products for bodybuilding and can be used to enhance physical performance. This study's aims were to validate a fast and sensitive detection method for IGF-I analogs and to evaluate their detectability after intramuscular administration in rats. The sample preparation consisted of an immunopurification on MSIA™ microcolumns using a polyclonal anti-human-IGF-I antibody. The target substances were then directly analyzed by nano-liquid chromatography coupled with high-resolution mass spectrometry. Abundant signs of lower quality, oxidized peptide forms were found in black market products, justifying the need to monitor at least both the native and mono-oxidized forms. The analytical performance of this method (linearity, carry over, detection limits, precision, specificity, recovery, and matrix effect) was studied by spiking the analogs into human serum. Following a single intramuscular administration (100 μg/kg) in rats, detection was evaluated up to 36 h after injection. While unchanged Des(1-3)-IGF-I and R 3 -IGF-I were detected until 24 h after administration, LongR 3 -IGF-I disappeared rapidly after 4 h. Des(1)-LongR 3 -IGF-I, a new N-terminal Long-R 3 -IGF-I degradation product, was detected in addition to Des(1-10)-LongR 3 -IGF-I and Des(1-11)-LongR 3- IGF-I: the latter was detected up to 16 h. The same products were found after in vitro incubation of the analogs in human whole blood, suggesting that observations in rats may be extrapolated to humans and that the validated method may be applicable to antidoping testing., (© 2021 John Wiley & Sons, Ltd.)

Context: Anorexia nervosa (AN) is prevalent in adolescent girls and is associated with bone impairment driven by hormonal alterations in nutritional deficiency., Objective: To assess the impact of estrogen replacement with and without recombinant human insulin-like growth factor-1 (rhIGF-1) administration on bone outcomes., Design: Double-blind, randomized, placebo-controlled 12-month longitudinal study., Participants: Seventy-five adolescent and young adult women with AN age 14 to 22 years. Thirty-three participants completed the study., Intervention: Transdermal 17-beta estradiol 0.1 mg/day with (i) 30 mcg/kg/dose of rhIGF-1 administered subcutaneously twice daily (AN-IGF-1+) or (ii) placebo (AN-IGF-1-). The dose of rhIGF-1 was adjusted to maintain levels in the upper half of the normal pubertal range., Main Outcome Measures: Bone turnover markers and bone density, geometry, microarchitecture, and strength estimates., Results: Over 12 months, lumbar areal bone mineral density increased in AN-IGF-1- compared to AN-IGF-1+ (P = 0.004). AN-IGF-1+ demonstrated no improvement in areal BMD in the setting of variable compliance to estrogen treatment. Groups did not differ for 12-month changes in bone geometry, microarchitecture, volumetric bone mineral density (vBMD), or strength (and results did not change after controlling for weight changes over 12 months). Both groups had increases in radial cortical area and vBMD, and tibia cortical vBMD over 12 months. Levels of a bone resorption marker decreased in AN-IGF-1- (P = 0.042), while parathyroid hormone increased in AN-IGF-1+ (P = 0.019). AN-IGF-1- experienced irregular menses more frequently than did AN-IGF-1+, but incidence of all other adverse events did not differ between groups., Conclusions: We found no additive benefit of rhIGF-1 administration for 12 months over transdermal estrogen replacement alone in this cohort of young women with AN., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The goals of this study are to develop a high purity patented silk fibroin (SF) film and test its suitability to be used as a slow-release delivery for insulin-like growth factor-1 (IGF-1). The release rate of the SF film delivering IGF-1 followed zero-order kinetics as determined via the Ritger and Peppas equation. The release rate constant was identified as 0.11, 0.23, and 0.09% h -1 at 37 °C for SF films loaded with 0.65, 6.5, and 65 pmol IGF-1, respectively. More importantly, the IGF-1 activity was preserved for more than 30 days when complexed with the SF film. We show that the IGF-1-loaded SF films significantly accelerated wound healing in vitro (BALB/3T3) and in vivo (diabetic mice), compared with wounds treated with free IGF-1 and an IGF-1-loaded hydrocolloid dressing. This was evidenced by a six-fold increase in the granulation tissue area in the IGF-1-loaded SF film treatment group compared to that of the PBS control group. Western blotting analysis also demonstrated that IGF-1 receptor (IGF1R) phosphorylation in diabetic wounds increased more significantly in the IGF-1-loaded SF films group than in other experimental groups. Our results suggest that IGF-1 sustained release from SF films promotes wound healing through continuously activating the IGF1R pathway, leading to the enhancement of both wound re-epithelialization and granulation tissue formation in diabetic mice. Collectively, these data indicate that SF films have considerable potential to be used as a wound dressing material for long-term IGF-1 delivery for diabetic wound therapy.

Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for 1 wk into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses. Late gestation fetal sheep received infusions with IGF-1 LR3 (IGF-1, n = 8), an analog of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON, n = 9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1, n = 8; CON, n = 7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1, n = 8; CON, n = 7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared with CON ( P = 0.0135 and P = 0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared with CON ( P = 0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses ( P = 0.0447). In summary, IGF-1 LR3 infusion for 1 wk into fetal sheep lowers insulin concentrations and reduces fetal GSIS. Impaired insulin secretion persists in isolated fetal islets indicating an intrinsic islet defect in insulin release when exposed to IGF-1 LR3 infusion for 1 wk. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in β-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth. NEW & NOTEWORTHY After a 1-wk infusion of IGF-1 LR3, late gestation fetal sheep had lower plasma insulin and glucose concentrations, reduced fetal glucose-stimulated insulin secretion, and decreased fractional insulin secretion from isolated fetal islets without differences in pancreatic insulin content.

Sevoflurane anesthesia is correlated with the generation of postoperative cognitive dysfunction. Insulin-like growth factor 1 (IGF-1) has important function in the nervous system development. Intravenously injected IGF-1 is reported to successfully pass the blood-brain barrier and perform neuroprotection effect in the brain. Memory and learning abilities were analyzed through Morris water maze task. Relative levels of protein were examined through Western blot and enzyme-linked immunosorbent assay (ELISA). Relative mRNA levels were shown through quantitative real-time polymerase chain reaction (qRT-PCR). IGF-1 expression in the plasma and hippocampus was downregulated in sevoflurane anesthesia-induced rats and rescued by intravenous IGF-1 injection. In aged rats, intravenous injection of IGF-1 alleviated sevoflurane-caused cognitive injuries and elevated TNF-α, IL-1β, and IL-6 levels in the plasma and hippocampus and rescued sevoflurane-depressed Akt phosphorylation. In conclusion, the administration of IGF-1 through intravenous injection alleviates sevoflurane anesthesia-mediated neuroinflammation and cognitive impairment in rats. The effects of IGF-1 in this process may depend on its function in regulating the PI3K/Akt signaling pathway. NEW & NOTEWORTHY IGF-1 expression was downregulated by sevoflurane anesthesia in rats and could be rescued by intravenous IGF-1 injection, which alleviated sevoflurane-caused cognitive injuries and enhanced inflammatory responses in aged rats. Intravenous injection of IGF-1 rescued sevoflurane-depressed Akt phosphorylation in aged rats.

Migraineurs experience increased oxidative stress which drives the initiation and maintenance of migraine-related pain in animal models and, by extension, migraine in humans. Oxidative stress augments calcitonin gene-related peptide (CGRP) levels, a mediator of migraine pain. Insulin-like growth factor-1 (IGF-1), a neuroprotective growth factor, reduces susceptibility to spreading depression, a preclinical model of migraine, in cultured brain slices by blocking oxidative stress and neuroinflammation from microglia. Similarly, nasal delivery of IGF-1 inhibits spreading depression in vivo. After recurrent cortical spreading depression, nasal administration of IGF-1 also significantly reduces trigeminal ganglion oxidative stress and CGRP levels as well as trigeminocervical c-Fos activation. Here, we probed for the impact of nasal IGF-1 pretreatment on trigeminal system activation using a second well-established preclinical model of migraine, systemic nitroglycerin injection. Adult male rats were treated with one of three doses of IGF-1 (37.5, 75 or 150 μg) and the optimal dose found in males was subsequently used for treatment of female rats. One day later, animals received an intraperitoneal injection of nitroglycerin. Measurements taken two hours later after nitroglycerin alone showed increased surrogate markers of trigeminal activation - oxidative stress and CGRP in the trigeminal ganglion and c-Fos in the trigeminocervical complex compared to vehicle control. These effects were significantly reduced at all doses of IGF-1 for trigeminal ganglion metrics of oxidative stress and CGRP and only at the lowest dose in both males and females for c-Fos. The latter inverted U-shaped or hormetic response is seen in enzyme-targeting drugs. While the specific mechanisms remain to be explored, our data here supports the ability of IGF-1 to preserve mitochondrial and antioxidant pathway homeostasis as means to prevent nociceptive activation in the trigeminal system produced by an experimental migraine model., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Insulin-like growth factor-1 (IGF-1) plays a key role in synaptic plasticity, spatial learning, and anxiety-like behavioral processes. While IGF-1 regulates neuronal firing and synaptic transmission in many areas of the central nervous system, its signaling and consequences on excitability, synaptic plasticity, and animal behavior dependent on the prefrontal cortex remain unexplored. Here, we show that IGF-1 induces a long-lasting depression of the medium and slow post-spike afterhyperpolarization (mAHP and sAHP), increasing the excitability of layer 5 pyramidal neurons of the rat infralimbic cortex. Besides, IGF-1 mediates a presynaptic long-term depression of both inhibitory and excitatory synaptic transmission in these neurons. The net effect of this IGF-1-mediated synaptic plasticity is a long-term potentiation of the postsynaptic potentials. Moreover, we demonstrate that IGF-1 favors the fear extinction memory. These results show novel functional consequences of IGF-1 signaling, revealing IGF-1 as a key element in the control of the fear extinction memory., Competing Interests: LM, JN, IM, JM, AM, MC, DF No competing interests declared, (© 2021, Maglio et al.)

Bone marrow mesenchymal stem cell (BMSC) transplantation is a promising treatment for ischemic stroke that carries a severe mortality and disability burden amongst the adult population globally. Thus far, BMSC transplantation has been insufficient for ameliorating neurological deficits resulting from cerebral ischemia. This shortcoming may be an outcome due to poor homing and viability of grafted cells in ischemic brain that limit the potential therapeutic benefits of BMSC transplantation. Insulin-like growth factor-1 (IGF-1), a potent anti-apoptotic agent, exerts neuroprotective effects in ischemic stroke as well as rescuing neuronal death in vitro. We hypothesized that IGF-1 could also protect BMSCs from apoptotic death, and examined whether the combination of BMSCs with IGF-1 can enhance functional recovery outcomes in mice following cerebral ischemia. Intranasal administration of BMSCs with IGF-1 was applied in a mouse focal ischemic stroke model. Our in vitro results indicated that BMSCs treated with IGF-1 exhibited less apoptotic death induced by oxygen-glucose deprivation (OGD), and an improved migratory capacity. At 14 days after ischemic insult, the combination of BMSCs with IGF-1 resulted in a larger number of NeuN/BrdU and Glut-1/BrdU co-labeled cells in the areas contiguous to the ischemic core than IGF-1 or BMSC treatment alone. Western blot assays demonstrated that the protein levels of BDNF, VEGF and Ang-1 were significantly upregulated in the peri-infarct region in the combination treatment group compared with single IGF- 1 or BMSC treatment. Co-administration of BMSCs and IGF-1 markedly increases local cerebral blood flow and promoted better functional behavior outcomes. These data suggest that intranasal delivery of BMSCs in conjunction with IGF-1 strengthened functional recovery following ischemia via increasing neurogenesis and angiogenesis, providing a novel optimized strategy for improving the therapeutic efficacy of BMSC transplantation for ischemia., (Copyright © 2020. Published by Elsevier Inc.)

Insulin-like growth factor-1 (IGF-1) is an important fetal growth factor. However, the role of fetal IGF-1 in increasing placental blood flow, nutrient transfer, and nutrient availability to support fetal growth and protein accretion is not well understood. Catheterized fetuses from late gestation pregnant sheep received an intravenous infusion of LR3 IGF-1 (LR3 IGF-1; n = 8) or saline (SAL; n = 8) for 1 wk. Sheep then underwent a metabolic study to measure uterine and umbilical blood flow, nutrient uptake rates, and fetal protein kinetic rates. By the end of the infusion, fetal weights were not statistically different between groups (SAL: 3.260 ± 0.211 kg, LR3 IGF-1: 3.682 ± 0.183; P = 0.15). Fetal heart, adrenal gland, and spleen weights were higher ( P < 0.05), and insulin was lower in LR3 IGF-1 ( P < 0.05). Uterine and umbilical blood flow and umbilical uptake rates of glucose, lactate, and oxygen were similar between groups. Umbilical amino acid uptake rates were lower in LR3 IGF-1 ( P < 0.05) as were fetal concentrations of multiple amino acids. Fetal protein kinetic rates were similar. LR3 IGF-1 skeletal muscle had higher myoblast proliferation ( P < 0.05). In summary, LR3 IGF-1 infusion for 1 wk into late gestation fetal sheep increased the weight of some fetal organs. However, because umbilical amino acid uptake rates and fetal plasma amino acid concentrations were lower in the LR3 IGF-1 group, we speculate that animals treated with LR3 IGF-1 can efficiently utilize available nutrients to support organ-specific growth in the fetus rather than by stimulating placental blood flow or nutrient transfer to the fetus. NEW & NOTEWORTHY After a 1-wk infusion of LR3 IGF-1, late gestation fetal sheep had lower umbilical uptake rates of amino acids, lower fetal arterial amino acid and insulin concentrations, and lower fetal oxygen content; however, LR-3 IGF-1-treated fetuses were still able to effectively utilize the available nutrients and oxygen to support organ growth and myoblast proliferation.

The role and significance of liver-derived cytokines in cancer-associated cachexia syndrome remain elusive. Here we report that combinatorial counterbalances of the leptin and Igf1 signaling pathways in hepatocellular carcinoma (HCC) models significantly relieves cachexia. Double transgenic zebrafish models of HCC that stably displayed focal lesions, anorexia, and wasting of adipose and muscle tissues were first generated. Knockout of lepr or mc4r from these zebrafish partially restored appetite and exerted moderate or no effect on tissue wasting. However, genetic replenishment of Igf1 in a lepr-mutant background effectively relieved the cachexia-like phenotype without affecting tumor growth. Similarly, administration of napabucasin, a Stat3/Socs3 inhibitor, on the zebrafish HCC model, mammalian cell lines with exogenous IGF1, and two mouse xenograft models restored insulin sensitivity and rescued the wasting of nontumor tissues. Together, these results describe the synergistic impact of leptin and Igf1 normalization in treating certain HCC-associated cachexia as a practical strategy. SIGNIFICANCE: Disruption of leptin signaling with normalized Igf1 expression significantly rescues anorexia, muscle wasting, and adipose wasting in Ras- and Myc-driven zebrafish models of HCC., (©2020 American Association for Cancer Research.)

In vitro embryo production systems are limited by their inability to consistently produce embryos with the competency to develop to the blastocyst stage, survive cryopreservation, and establish a pregnancy. Previous work identified a combination of three cytokines [fibroblast growth factor 2 (FGF2), leukemia inhibitory factor (LIF), and insulin-like growth factor 1 (IGF1)], called FLI, that we hypothesize improve preimplantation development of bovine embryos in vitro. To test this hypothesis, FLI was supplemented into oocyte maturation or embryo culture medium. Embryos were produced in vitro using abattoir-derived oocytes and fertilized with sperm from a single bull known to have high fertility. After an 18-20 h fertilization period, putative zygotes were cultured in synthetic oviductal fluid (SOF) for 8 days. The addition of FLI to the oocyte maturation medium increased (P < 0.05) the dissociation of transzonal projections at 12, 18, and 24 h of maturation, as well as, the proportion of oocytes that reached the metaphase II stage of meiosis. Additionally, lipid content was decreased (P < 0.05) in the blastocyst stage embryo. The addition of FLI during the culture period increased development to the blastocyst stage, cytoskeleton integrity, and survival following slow freezing, as well as, decreased post thaw cell apoptosis (P < 0.05). In conclusion, the supplementation of these cytokines in vitro has the potential to alleviate some of the challenges associated with the cryo-survival of in vitro produced bovine embryos through improving embryo development and embryo quality., Competing Interests: RSP and LDS are named on a U.S. patent application for the use of FLI in embryo culture media (US Patent Application No. 16/891,776 - Title: Medium Supplement to Increase the Efficiency of Oocyte Maturation and Embryo Culture In Vitro). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The use of injectable scaffolds to repair the infarcted heart is receiving great interest. Thermosensitive polymers, in situ polymerization, in situ cross-linking, and self-assembling peptides are the most investigated approaches to obtain injectability.Aim of the present work was the preparation and characterization of a novel bioactive scaffold, in form of injectable microspheres, for cardiac repair. Gellan/gelatin microspheres were prepared by a water-in-oil emulsion and loaded by adsorption with Insulin-like growth factor 1 to promote tissue regeneration. Obtained microspheres underwent morphological, physicochemical and biological characterization, including cell culture tests in static and dynamic conditions and in vivo tests. Morphological analysis of the microspheres showed a spherical shape, a microporous surface and an average diameter of 66 ± 17µm (under dry conditions) and 123 ± 24 µm (under wet conditions). Chemical Imaging analysis pointed out a homogeneous distribution of gellan, gelatin and Insulin-like growth factor-1 within the microsphere matrix. In vitro cell culture tests showed that the microspheres promoted rat cardiac progenitor cells adhesion, and cluster formation. After dynamic suspension culture within an impeller-free bioreactor, cells still adhered to microspheres, spreading their cytoplasm over microsphere surface. Intramyocardial administration of microspheres in a cryoinjury rat model attenuated chamber dilatation, myocardial damage and fibrosis and improved cell homing.Overall, the findings of this study confirm that the produced microspheres display morphological, physicochemical, functional and biological properties potentially adequate for future applications as injectable scaffold for cardiac tissue engineering.

Introduction: Hypophysiotropic gonadotropin-releasing hormone (GnRH) neurons orchestrate various physiological events that control the onset of puberty. Previous studies showed that insulin-like growth factor 1 (IGF-1) induces the secretion of GnRH and accelerates the onset of puberty, suggesting a regulatory role of this hormone upon GnRH neurons., Methods: To reveal responsiveness of GnRH neurons to IGF-1 and elucidate molecular pathways acting downstream to the IGF-1 receptor (IGF-1R), in vitro electrophysiological experiments were carried out on GnRH-GFP neurons in acute brain slices from prepubertal (23-29 days) and pubertal (50 days) male mice., Results: Administration of IGF-1 (13 nM) significantly increased the firing rate and frequency of spontaneous postsynaptic currents and that of excitatory GABAergic miniature postsynaptic currents (mPSCs). No GABAergic mPSCs were induced by IGF-1 in the presence of the GABAA-R blocker picrotoxin. The increase in the mPSC frequency was prevented by the use of the IGF-1R antagonist, JB1 (1 µM), or the intracellularly applied PI3K blocker (LY294002, 50 µM), showing involvement of IGF-1R and PI3K in the mechanism. Blockade of the transient receptor potential vanilloid 1, an element of the tonic retrograde endocannabinoid machinery, by AMG9810 (10 µM) or antagonizing the cannabinoid receptor type-1 by AM251 (1 µM) abolished the effect., Discussion/conclusion: These findings indicate that IGF-1 arrests the tonic retrograde endocannabinoid pathway in GnRH neurons, and this disinhibition increases the release of GABA from presynaptic terminals that, in turn, activates GnRH neurons leading to the fine-tuning of the hypothalamo-pituitary-gonadal axis., (© 2020 S. Karger AG, Basel.)

Insulin-like growth factor 1 (IGF-1) is indicated for growth failure in pediatric patients with primary IGF-1 deficiency and for patients with neutralizing antibodies to growth hormone. IGF-1 was cloned, expressed and purified in-house. Preliminary stability studies prior to the transdermal delivery experiments showed that although stable in contact with stratum corneum, the solution concentration of IGF-1 decreased to 23.63 ± 2.48 and 21.58 ± 2.62% of the initial value upon exposure for 8 h to porcine dermis of 250 and 750 µm thickness. This led to an investigation into how it might be possible to improve the stability of IGF-1 in the presence of porcine/human skin. The stability of IGF-1 in the presence of dermis improved upon heating the skin samples at 60 °C for 2 min suggesting that IGF-1 was subject to enzymatic degradation. Although addition of the protease inhibitor, phenylmethanesulfonyl fluoride (PMSF) alone, did not improve stability, the use of a protease inhibitor cocktail completely blocked proteolytic degradation of IGF-1; the solution concentration after an 8 h exposure to porcine skin was equivalent to the initial level (103.87 ± 9.15%). The results obtained with porcine skin were confirmed with human skin (IGF-1 recovery was 99.31 ± 9.98%). These findings suggest that the inclusion of protease inhibitor cocktails may be useful in limiting the degradation of therapeutic proteins during iontophoresis and transdermal delivery in general - this could be of particular interest for local delivery of peptide/protein therapeutics for dermatological applications., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

The hair follicle (HF) growth cycle is a complex, multistep biological process, for which dysfunction affects hair-related diseases in humans and wool production in animals. In this study, a treatment combination of 10 ng/mL insulin-like growth factor-1 (IGF-1) and 20 ng/mL epidermal growth factor (EGF) significantly increased the elongation length of hair shafts for cultured HFs. The combined treatment of IGF-1 and EGF enhanced the proliferation of HFs and promoted HF growth and development in vitro. In vivo, the combined treatment of IGF-1 and EGF was subcutaneously injected into the dorsal skin in HF synchronized rabbits. The IGF-1 and EGF combination promoted the transition of the hair cycle from telogen to anagen and stimulated the growth of hair shafts. This IGF-1 and EGF combination maintained the structure of the HF and enhanced the cell proliferation of outer root sheaths and the dermal papilla within rabbit skin. The combined treatment of IGF-1 and EGF regulated HF-related genes, including LEF1 , CCND1 and WNT2 , suggesting that IGF-1 and EGF play a positive role in HF growth and development. Utilization of the combined IGF-1 and EGF treatment may assist with hair and wool production and HF related diseases in mammals.

Mechanistic target of rapamycincomplex 1 (mTORC1) integrates various environmental signals to regulate cell growth and metabolism. mTORC1 activity is sensitive to changes in amino acid levels. Here, we investigated the effect of lysine on mTORC1 activity in non-small cell lung cancer (NSCLC) cells. Lysine deprivation suppressed mTORC1 activity and lysine replenishment restored the decreased mTORC1 activity in lysine-deprived cells. Supplementing growth factors, such as insulin growth factor-1 or insulin restored the decreased mTORC1 activity in serum-deprived cells. However, in serum/lysine-deprived cells, supplementing growth factors was not sufficient to restore mTORC1 activity, suggesting thatgrowth factors could not activate mTORC1 efficiently in the absence of lysine. General control nonderepressible 2 and AMP-activated protein kinase were involved in lysine deprivation-mediated inhibition of mTORC1. Taken together, these results suggest that lysine might play role in the regulation of mTORC1 activation in NSCLC cells., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The aim of this study is to fabricate and test a 3D-printed PCL scaffold incorporating IGF-1-releasing PLGA nanoparticles for cartilage tissue engineering. IGF-1 loaded PLGA nanoparticles were produced by the double-emulsion method, and were incorporated onto 3D printed PCL scaffolds via PDA. Particle size, loading effciency (LE) and encapsulation effciency (EE) of the nanoparticles were examined. SEM, pore size, porosity, compression testing, contact angle, IGF-1 release kinetics of the composite scaffolds were also determined. For cell culture studies, CCK-8, Live/dead, MTT, GAG content and expression level of chondrocytes specific proteins and genes and HIF-1α were also tested. There was no difference of the nanoparticle size. And the LE and EE of IGF-1 in PLGA nanoparticles was about 5.53 ± 0.12% and 61.26 ± 2.71%, respectively. There was a slower, sustained release for all drug-loaded nanoparticles PLGA/PDA/PCL scaffolds. There was no difference of pore size, porosity, compressive strength of each scaffold. The contact angles PCL scaffolds were significant decreased when coated with PDA and PLGA nanoparticales. ( p  < .05) Live/dead staining showed more cells attached to the IGF-1 PLGA/PDA/PCL scaffolds. The CCK-8 and MTT assay showed higher cell proliferation and better biocompatibility of the IGF-1 PLGA/PDA/PCL scaffolds. ( p  < .05) GAG content, chondrogenic protein and gene expression level of SOX-9, COL-II, ACAN, and HIF pathway related gene (HIF-1α) were significantly higher in IGF-1 PLGA/PDA/PCL scaffolds group compared to other groups. ( p  < .05) IGF-1 PLGA/PDA/PCL scaffolds may be a better method for sustained IGF-1 administration and a promising scaffold for cartilage tissue engineering.

Exogenous dual delivery of progenitor cell population and therapeutic growth factors (GFs) is one of alternative tissue engineering strategies for osteochondral tissue regeneration. In the present study, an implantable dual delivery platform was developed using coacervates (Coa) (i.e., a tertiary complex of poly(ethylene argininylaspartate diglyceride) (PEAD) polycation, heparin, and cargo insulin-like growth factor-1 (IGF-1), in thiolated gelatin (gelatin-SH)/ poly(ethylene glycol) diacrylate (PEGDA) interpenetrating network (IPN) hydrogels. Since Coa is able to protect cargo GF and maintain its long-term bioactivity, it is speculated that Coa-mediated delivery of chondrogenic factor IGF-1 with the aid of adipose-derived stem cells (ADSCs) would synergistically facilitate osteochondral tissue repair during physiological regeneration process. Our results indicate that gelatin-SH/PEGDA IPN hydrogels demonstrated biocompatibility and mechanical properties for a possible long-term transplantation, and PEAD-base Coa exhibited a sustained release of bioactive IGF-1 over 3 weeks. Subsequently, released IGF-1 from Coa could effectively induce chondrogenic differentiation of embedded ADSCs in the hydrogel, by showing enhanced glycosaminoglycan deposition and expression of chondrogenesis-associated genes. More importantly, at 12 weeks post-implantation in a rabbit full thickness osteochondral defect model, the quality of regenerative tissues in both chondral and subchondral layers was significantly improved in dual delivery of ADSC and IGF-1 in Coa encapsulated in gelatin-SH/PEGDA IPN hydrogels, as compared with a single delivery of ADSC only and a dual delivery without Coa. Therefore, we conclude that our Coa-embedded composite hydrogel platform could effectively augment osteochondral tissue regeneration holds promise for a feasible osteoarthritis therapeutic application., (Copyright © 2020. Published by Elsevier B.V.)

The effects of adipokine administration to the hypothalamic preoptic area (POA), which is one of the body temperature (BT) regulation centers in the central nervous system, on BT were investigated in male Wistar rats. BT was measured in conscious rats using telemetry. Insulin-like growth factor-1 (IGF-1), interleukin-1β (IL-1β), monocyte chemoattractant protein-1 and lipocalin-2 produced hyperthermia, and the effects induced by IL-1β (25 ng) and IGF-1 (5 μg) were sustainable and remarkable. IL-6 did not show any significant effect. The IGF-1-induced effect was inhibited by pretreatment with IGF binding protein 3 (IGFBP3) or NVP-AEW541 (NVP, a selective inhibitor of type 1 IGF receptor tyrosine kinase, IGF1R TK). NVP-induced inhibition was observed only in the early phase of IGF-1-induced hyperthermia. In addition, IGF-1 increased the IL-1β concentration in the microdialysate of POA perfusion, but did not increase the IL-1β concentration in the plasma or the PGE 2 concentration in the microdialysate. These findings suggested that IGF-1 produced hyperthermia, which was mediated, at least a part, through an increased IL-1β concentration after activation of IGF1R TK in the POA, and the IGF-IGFBP system possibly participates in BT homeostasis in the POA., Competing Interests: Declaration of Competing Interest The authors indicated no potential conflicts of interest., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

The objective of this study was to evaluate the effects of in ovo injection with glycerol (GLY) and insulin-like growth factor (IGF-I) on hatchability, biochemical parameters, intestinal morphometry, performance, and carcass characteristics of broiler chickens. A total of 400 fertilised eggs were distributed into five experimental groups. The treatments were arranged as non-injected (control), saline solution injected (0.9% NaCl solution), GLY solution injected (10 nmol/ml), IGF-I solution injected (100 ng/ml), and GLY + IGF-I solution injected. At 17.5 d of incubation, 0.5 ml of each solution was injected into the amniotic fluid of each egg of the injected groups. The injection of different solutions did not influence the hatchability and incubation time of the eggs. Compared to intact eggs, IGF-I and IGF-I+ GLY increased ( p  < 0.01) the blood IGF-I at hatching. Higher hepatic glycogen was observed ( p  < 0.05) with GLY or IGF-I. The tested substances decreased ( p  = 0.02) the fructose 1,6-biphosfate phosphatase activity but did not affect glycaemia. No difference in performance was observed in the first week. Higher feed intake and weight gain with lower feed conversion ratio was obtained ( p  < 0.05) with IGF-I at 14 d. At 21 d, higher weight gain was obtained ( p  = 0.05) with IGF-I, GLY, IGF-I, and GLY + IGF-I, resulting ( p  < 0.01) in birds with greater weight gain at 35 and 42 d of age. GLY provided higher villus height in the ileum at hatching and at 7 d of age. The tested solutions increased the relative weight of the liver at hatching. At 42 d of age, no carcass characteristics were influenced. It is concluded that GLY and IGF-I, together or separately, can be used in the in ovo feeding to improve the post-hatch performance of broilers, without affecting hatchability and carcass composition.

Background/aim: The insulin-like growth factor type 1 receptor (IGF-1R) is overexpressed in myelodysplastic syndrome (MDS) cells, and 765IGF-Methotrexate (IGF-MTX) is a conjugate of methotrexate and a variant of insulin-like growth factor-1 (IGF-1) designed to selectively target cancer cells through binding to IGF-1R. The aim of this study was to determine whether IGF-MTX would be effective to treat MDS., Patients and Methods: In this phase I clinical trial, two patients with high grade MDS or oligoblastic acute myeloid leukemia (O-AML) that had failed standard therapy were treated with IGF-MTX., Results: No dose-limiting toxicity was observed. Both patients had stable or improved cell counts and CD34+ myelodysplastic cell counts and exceeded their life expectancy (both alive at 1.9 years despite a life expectancy of less than 6 months). Bone marrow blast counts decreased from 22% to 5% in one patient, and from 17% to 16% in the other., Conclusion: In conclusion, IGF-MTX at 0.20 μM equivalents per kg was well tolerated, caused no cytopenia, and produced stable disease and extension of life., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Mesenchymal stem cell (MSC)-based therapies hold great promise for the treatment of inflammatory bowel disease (IBD). In order to optimize and maximize the therapeutic benefits of MSCs, we investigated whether cotransplantation of a chitosan (CS)-based injectable hydrogel with immobilized IGF-1 C domain peptide (CS-IGF-1C) and human placenta-derived MSCs (hP-MSCs) could ameliorate colitis in mice. Methods: IGF-1C hydrogel was generated by immobilizing IGF-1C to CS hydrogel. Colitis was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. We initially applied hP-MSCs and CS-IGF-1C hydrogel for the treatment of colitis by in situ injection, and molecular imaging methods were used for real-time imaging of reactive oxygen species (ROS) and tracking of transplanted hP-MSCs by bioluminescence imaging (BLI). Furthermore, the effects of CS-IGF-1C hydrogel on prostaglandin E 2 (PGE 2 ) secretion of hP-MSCs and polarization of M2 macrophages were investigated as well. Results: The CS-IGF-1C hydrogel significantly increased hP-MSC proliferation and promoted the production of PGE 2 from hP-MSCs in vitro . Moreover, in vivo studies indicated that the CS-IGF-1C hydrogel promoted hP-MSC survival as visualized by BLI and markedly alleviated mouse colitis, which was possibly mediated by hP-MSC production of PGE 2 and interleukin-10 (IL-10) production by polarized M2 macrophages. Conclusions: The CS-IGF-1C hydrogel improved the engraftment of transplanted hP-MSCs, ameliorated inflammatory responses, and further promoted the functional and structural recovery of colitis through PGE 2 -mediated M2 macrophage polarization. Molecular imaging approaches and therapeutic strategies for hydrogel application provide a versatile platform for exploring the promising therapeutic potential of MSCs in the treatment of IBD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Laron Syndrome (LS), (OMIM# 262500), a rare recessively inherited disease caused by deletions or mutations of the GH receptor, gene characterized by dwarfism with low or undetectable serum IGF-I in the presence of high serum GH. In addition to dwarfism, the IGF-I deficiency leads to metabolic abnormalities including aberrations in protein biosynthesis and homeostasis. The only available treatment for LS patients is (r)IGF-I administration. The present study was aimed to determine the plasma concentrations of specific amino acids and their metabolites in the blood of untreated and IGF-I-treated LS patients. The study involved a total of 10 LS patients (3 untreated and 7 treated), 2 heterozygote mothers and 3aged subjects. Forty healthy boys and girls served as controls. The analysis of amino acids and their metabolites was performed using the LC-MS/MS analysis and Waters Acc-Q Tag ultra-derivatization kit. Serum IGF-I levels were measured by a one-step sandwich chemiluminescence immunoassay. The results revealed that long-term IGF-I deficiency in LS patients led to abnormal changes in the plasma amino acids metabolism, such as low levels of plasma citrulline, sarcosine and taurine that increased upon IGF-I replacement. The plasma amino acid levels of the heterozygous family members resembled those of the untreated LS patients, whereas the pattern in the 2 double heterozygote sisters previously treated with IGF-I resembled that of the presently IGF-I-treated patients. In addition, plasma ɑ-amino adipic acid levels were elevated in both untreated and IGF-I-treated patients. In summary our data revealed that LS patients, a condition associated with congenital IGF-I deficiency, have an abnormal plasma amino acid metabolism that is partially restored by IGF-I treatment., Competing Interests: Declaration of Competing Interest Authors have nothing to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Both rhGH and rhIGF-I are signaling molecules with the capacity to restore the rate of growth in certain subsets of slowly growing children. In some instances, heights attained at or near the time of cessation of linear growth are indistinguishable from the height distribution of the community as a whole or from the height distribution expected based on the heights of biological parents. The GH: IGF-I signaling system is sequential, forming a continuous loop wherein GH will stimulate production of IGF-I and IGF-I will inhibit production of GH. This feature suggests that a deficiency of GH will be accompanied by a deficiency of IGF-I and that treatment of GH deficiency with rhGH will restore IGF-I and the subnormal growth of combined GH: IGF-I deficiency. Although logical, this proposition is not always true. rhGH and rhIGF-I are distinct polypeptides, with distinct cell surface receptors and distinct intracellular signaling pathways both capable of amplifying distinct, yet overlapping, patterns of gene replication, protein synthesis and metabolic activities. These features suggest that neither treatment with rhGH nor rhIGF-I alone will invariably recapitulate the combined activities of the GH: IGF-I system, At the present time, this proposition appears both logical and true. The possibility that combined rhGH and rhIGF-I treatment can accomplish that which neither monotherapy can has been examined in gene knock-out experiments in animals and direct comparisons of GH, IGF-I and combined GH: IGF- treatments in animals and in children with short stature, normal GH and low IGF-I (primary IGF-I deficiency). In these experimental models, the growth rates with combined rhGH and rhIGF-I treatment exceed those of either monotherapy. The extent to which this proposition can be generalized to various short stature populations remains to be determined., (Copyright © 2020. Published by Elsevier Ltd.)

Growth hormone (GH) and insulin like growth factor-I (IGFI) are key bone trophic hormones, whose rising levels during puberty are critical for pubertal bone accrual. Conditions of GH deficiency and genetic resistance impact cortical and trabecular bone deleteriously with reduced estimates of bone strength. In humans, conditions of undernutrition (as in anorexia nervosa (AN), or subsequent to chronic illnesses) are associated with low IGF-I levels, which correlate with disease severity, and also with lower bone mineral density (BMD), impaired bone structure and lower strength estimates. In adolescents and adults with AN, studies have demonstrated a nutritionally acquired GH resistance with low IGF-I levels despite high concentrations of GH. IGF-I levels go up with increasing body weight, and are associated with rising levels of bone turnover markers. In short-term studies lasting 6-10 days, recombinant human IGF-I (rhIGF-I) administration in physiologic replacement doses normalized IGF-I levels and increased levels of bone formation markers in both adults and adolescents with AN. In a randomized controlled trial in adults with AN in which participants were randomized to one of four arms: (i) rhIGF-I with oral estrogen-progesterone (EP), (ii) rhIGF-I alone, (iii) EP alone, or (iv) neither for 9 months, a significant increase in bone formation markers was noted in the groups that received rhIGF-I, and a significant decrease in bone resorption markers in the groups that received EP. The group that received both rhIGF-I and EP had a significant increase in bone density at the spine and hip compared to the group that received neither. Side effects were minimal, with no documented fingerstick glucose of <50 mg/dl. These data thus suggest a potential role for rhIGF-I administration in optimizing bone accrual in states of undernutrition associated with low IGF-I., Competing Interests: Declaration of Competing Interest Dr. Misra has received grant support from Novo-Nordisk and also served on the Scientific Advisory Board for this company. She is a consultant for Sanofi., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Osteoarthritis (OA) of the temporomandibular joint (TMJ) elicits cartilage and subchondral bone defects. Growth hormone (GH) promotes chondrocyte growth. The aim of this study was to evaluate the efficacy of intra-articular injections of GH to treat TMJ-OA., Materials and Methods: Monosodium iodoacetate (MIA) was used to induce OA in the TMJs of rats. After confirming the induction of OA, recombinant human GH was injected into the articular cavities of rats. Concentrations of GH and IGF-1 were measured in the blood and synovial fluid, and OA grades of cartilage and subchondral bone degradation were recorded by histological examination and micro-computed tomography., Results: MIA-induced OA in the rat TMJ upregulated insulin-like growth factor-1 (IGF-1) rather than GH levels. GH and IGF-1 concentrations were increased after local injection of GH, compared with controls. Locally injected GH lowered osteoarthritic scores in the cartilage and subchondral bone of the TMJ., Conclusion: Intra-articular injection of GH improved OA scores in rat TMJs in both cartilage and subchondral bone of the condyles without affecting condylar bone growth. These results suggest that intra-articular injection of human GH could be a suitable treatment option for TMJ-OA patients in the future., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Migraineurs can show brain hyperexcitability and oxidative stress that may promote headache. Since hyperexcitability can enhance oxidative stress which promotes hyperexcitability, ending this feed-back loop may reduce migraine. Neocortical spreading depression, an animal model of migraine begins with hyperexcitability and triggers oxidative stress in the neocortical area involved and in the trigeminal system, which is important to pain pathway nociceptive activation in migraine. Additionally, oxidative stress causes increased trigeminal ganglion calcitonin gene-related peptide release and oxidative stress can reduce spreading depression threshold. Insulin-like growth factor-1 significantly protects against spreading depression in vitro by reducing oxidative stress and it is effective against spreading depression after intranasal delivery to animals. Here, we used adult male rats and extend this work to study the trigeminal system where insulin-like growth factor-1 receptors are highly expressed. Recurrent neocortical spreading depression significantly increased surrogate markers of trigeminal activation - immunostaining for trigeminal ganglion oxidative stress, calcitonin gene related peptide levels and c-fos in the trigeminocervical complex versus sham. These effects were significantly reduced by intranasal delivery of insulin-like growth factor-1 a day before recurrent neocortical spreading depression. Furthermore, intranasal treatment with insulin-like growth factor-1 significantly reduced naïve levels of trigeminal ganglion calcitonin gene related peptide versus sham with no impact on blood glucose levels. Intranasal delivery of insulin-like growth factor-1 not only mitigates neocortical spreading depression, a cause of migraine hyperexcitability modeled in animals, but also when neocortical spreading depression is triggered by supra-threshold stimuli, insulin-like growth factor-1 effectively reduces nociceptive activation in the trigeminal system., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Fetal growth restriction (FGR) is associated with compromised growth and metabolic function throughout life. Intrauterine therapy of FGR with intra-amniotic insulin-like growth factor-1 (IGF1) enhances fetal growth and alters perinatal metabolism and growth in a sex-specific manner, but the adult effects are unknown. We investigated the effects of intra-amniotic IGF1 treatment of FGR on adult growth and body composition, adrenergic sensitivity, and glucose-insulin axis regulation. Placental embolization-induced FGR was treated with four weekly doses of 360 µg intra-amniotic IGF1 (FGRI) or saline (FGRS). Offspring were raised to adulthood (18 mo: FGRI, n = 12 females, 12 males; FGRS, n = 13 females, 10 males) alongside offspring from unembolized and untreated sheep (CON; n = 12 females, 21 males). FGRI females had increased relative lean mass compared with CON but not FGRS ( P < 0.05; 70.6 ± 8.2% vs. 61.4 ± 8.2% vs. 67.6 ± 8.2%), decreased abdominal adipose compared with CON and FGRS ( P < 0.05; 43.7 ± 1.2% vs. 49.3 ± 0.9% vs. 48.5 ± 1.0%), increased glucose utilization compared with FGRS but not CON ( P < 0.05; 9.6 ± 1.0 vs. 6.0 ± 0.9 vs. 7.6 ± 0.9 mg·kg -1 ·min -1 ), and increased β-hydroxybutyric acid:nonesterified fatty acid ratio in response to adrenaline compared with CON and FGRS ( P < 0.05; 3.9 ± 1.4 vs. 1.1 ± 1.4 vs. 1.8 ± 1.4). FGRS males were smaller and lighter compared with CON but not FGRI ( P < 0.05; 86.8 ± 6.3 vs. 93.5 ± 6.1 vs. 90.7 ± 6.3 kg), with increased peak glucose concentration (10%) in response to a glucose load but few other differences. These effects of intra-amniotic IGF1 therapy on adult body composition, glucose-insulin axis function, and adrenergic sensitivity could indicate improved metabolic regulation during young adulthood in female FGR sheep.

Human insulin-like growth factor-1 (IGF-1) plays important roles in development and regeneration of skeletal muscles and bones but requires daily injections or surgical implantation. Current clinical IGF-1 lacks e-peptide and is glycosylated, reducing functional efficacy. In this study, codon-optimized Pro-IGF-1 with e-peptide (fused to GM1 receptor binding protein CTB or cell penetrating peptide PTD) was expressed in lettuce chloroplasts to facilitate oral delivery. Pro-IGF-1 was expressed at high levels in the absence of the antibiotic resistance gene in lettuce chloroplasts and was maintained in subsequent generations. In lyophilized plant cells, Pro-IGF-1 maintained folding, assembly, stability and functionality up to 31 months, when stored at ambient temperature. CTB-Pro-IGF-1 stimulated proliferation of human oral keratinocytes, gingiva-derived mesenchymal stromal cells and mouse osteoblasts in a dose-dependent manner and promoted osteoblast differentiation through upregulation of ALP, OSX and RUNX2 genes. Mice orally gavaged with the lyophilized plant cells significantly increased IGF-1 levels in sera, skeletal muscles and was stable for several hours. When bioencapsulated CTB-Pro-IGF-1 was gavaged to femoral fractured diabetic mice, bone regeneration was significantly promoted with increase in bone volume, density and area. This novel delivery system should increase affordability and patient compliance, especially for treatment of musculoskeletal diseases., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The leptin receptor-deficient knockout (db/db) mouse is a well-established model for studying type II diabetes mellitus (T2DM). T2DM is an important risk factor of intervertebral disc degeneration (IVDD). Although the relationship between type I diabetes and IVDD has been reported by many studies, few studies have reported the effects of T2DM on IVDD in db/db mice model., Methods: Mice were separated into 3 groups: wild-type (WT), db/db, and IGF-1 groups (leptin receptor-deficient mice were treated with insulin-like growth factor-1 (IGF-1). To observe the effects of T2DM and glucose-lowering treatment on IVDD, IGF-1 injection was used. The IVD phenotype was detected by H&E and safranin O fast green staining among db/db, WT and IGF-1 mice. The levels of blood glucose and weight in mice were also recorded. The changes in the mass of the trabecular bone in the fifth lumbar vertebra were documented by micro-computed tomography (micro-CT). Tunnel assays were used to detect cell apoptosis in each group., Results: The weight of the mice were 27.68 ± 1.6 g in WT group, which was less than 57.56 ± 4.8 g in db/db group, and 52.17 ± 3.7 g in IGF-1 injected group (P < 0.05). The blood glucose levels were also significantly higher in the db/db mice group. T2DM caused by leptin receptor knockout showed an association with significantly decreased vertebral bone mass and increased IVDD when compared to WT mice. The db/db mice induced by leptin deletion showed a higher percentage of MMP3 expression as well as cell apoptosis in IVDD mice than WT mice (P < 0.05), while IGF-1 treatment reversed this situation (P < 0.05)., Conclusions: T2DM induced by leptin receptor knockout led to IVDD by increasing the levels of MMP3 and promoting cell apoptosis. IGF-1 treatment partially rescue the phenotype of IVDD induced by leptin receptor knockout.

Background and Aims: Cardiovascular diseases are the main cause of mortality in obesity. Despite advanced understanding, the mechanisms that regulate cardiac progenitor cells (CPC) survival in pathological conditions are not clear. Low IGF-1 plasma levels are correlated to obesity, cardiomyopathy and CPC death, so this work aimed to investigate IGF-1 therapeutic potential on cardiomyopathy and its relationship with the survival, proliferation and differentiation of CPC in Western diet-induced obesity., Methods and Results: Male Swiss mice were divided into control group (CG, n = 8), fed with standard diet; and obese group (OG, n = 16), fed with Western diet, for 12 weeks. At 11th week, OG was subdivided to receive a daily subcutaneous injection of human recombinant IGF-1 (100 μg.Kg -1 ) for seven consecutive days (OG + IGF1, n = 8). Results showed that IGF-1 therapy improved the metabolic parameters negatively impacted by western diet in OG, reaching levels similar to CG. OG + IGF-1 also demonstrated restored heart energetic metabolism, fibrosis resolution, decreased apoptosis level, restored cardiac gap junctions and intracellular calcium balance. Cardiomyopathy improvement was accompanied by increased CPC survival, proliferation and newly cardiomyocytes formation related to increased pAkt/Akt ratio., Conclusion: These results suggest that only one week of IGF-1 therapy has cardioprotective effects through Akt pathway upregulation, ensuring CPC survival and differentiation, contributing to heart failure rescue., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a growing problem worldwide, and there are currently no effective treatments for this devastating disease. The neurotrophic growth factors insulin and insulin-like growth factor-I (IGF-I) are currently being investigated as potential therapeutic approaches for AD in preclinical and clinical studies. However, given that the metabolic syndrome (MetS) and diabetes are risk factors for AD, it is unknown how associated insulin resistance (IR) in the brain may impact the effectiveness of these therapies for AD. In this report, we therefore investigated the mechanisms underlying the effects of insulin and IGF-I on AD-associated pathology in the context of IR, with particular emphasis on phosphorylation of amyloid precursor protein (APP), a key step in promoting amyloid plaque formation in AD. Both insulin and IGF-I decreased APP phosphorylation in cultured primary cortical neurons, supporting their therapeutic use in AD. Induction of IR blocked the beneficial effect of insulin and reduced the effect of IGF-I on APP dephosphorylation. These effects were mediated by the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (Akt) pathway, as inhibition of this pathway during IR restored the effect of IGF-I on APP dephosphorylation. Finally, we explored the translational relevance of these results in vivo by demonstrating that high fat diet fed mice, a robust model of IR and MetS, exhibited the expected increased brain APP phosphorylation. Overall, these data suggest that the beneficial therapeutic effect of insulin and IGF-I on APP phosphorylation is negatively impacted by IR, and suggest that insulin and IGF-I alone may not be appropriate therapies for AD patients with IR, MetS, or diabetes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The onset of puberty is the result of an increase in secretion of hypothalamic gonadotrophin-releasing hormone (GnRH). This action is a result of not only the development of stimulatory inputs to its release, but also the gradual decrease in inhibitory inputs that restrain release of the peptide prior to pubertal onset. Dynorphin (DYN) is one of the inhibitory inputs produced in the medial basal hypothalamus (MBH); however, little is known about what substance(s) control its prepubertal synthesis and release. Because neurokinin B (NKB) increases in the hypothalamus as puberty approaches, we considered it a candidate for such a role. An initial study investigated the acute effects of an NKB agonist, senktide, on the secretion of DYN from MBH tissues incubated in vitro. In other experiments, central injections of senktide were administered to animals for 4 days then MBHs were collected for assessment of DYN synthesis or for the in vitro secretion of both DYN and GnRH. Because insulin-like growth factor (IGF)-1 has been shown to play an important role at puberty, additional animals received central injections of this peptide for 4 days to assess NKB and DYN synthesis or the in vitro secretion of NKB. The results obtained show that senktide administration up-regulates the NKB receptor protein, at the same time as suppressing the DYN and its receptor. Senktide consistently suppressed DYN and elevated GnRH secretion in the same tissue incubates from both the acute and chronic studies. IGF-1 administration caused an increase in NKB protein, at the same time as decreasing DYN protein. Furthermore, the central administration of IGF-1 caused an increase in NKB release, an action blocked by the IGF-1 receptor blocker, JB-1. These results indicate that the IGF-1/NKB pathway contributes to suppressing the DYN inhibitory tone on prepubertal GnRH secretion and thus facilitates the puberty-related increase in the release of GnRH to accelerate the onset of puberty., (© 2019 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Decreased mineral density is one of the major complications of anorexia nervosa. The phenomenon is even more pronounced when the disease occurs during adolescence and when the duration of amenorrhoea is long. The mechanisms underlying bone loss in anorexia are complex. Oestrogen deficiency has long been considered as the main factor, but cannot explain the phenomenon on its own. The essential role of nutrition-related factors-especially leptin and adiponectin-has been reported in recent studies. Therapeutic strategies to mitigate bone involvement in anorexia are still a matter for debate. Although resumption of menses and weight recovery appear to be essential, they are not always accompanied by a total reversal of bone loss. There are no studies in the literature demonstrating that oestrogen treatment is effective, and the best results seem to have been obtained with agents that induce bone formation-such as IGF-1-especially when associated with oestrogen. As such, bone management in anorexia remains difficult, hence, the importance of early detection and multidisciplinary follow-up., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The objective of this study was to improve cartilage repair and integration using self-assembling KLD hydrogel functionalized with platelet-derived growth factor-BB and heparin-binding insulin-like growth factor-1 with associated enzymatic trypsin pre-treatment of the native cartilage. Bilateral osteochondral defects were created at the central portion of the femoral trochlear groove of 48 skeletally mature, white New Zealand rabbits. One limb received a randomly assigned treatment and the contralateral limb served as the control. Treated defects were exposed to trypsin for 2 min and filled with self-assembling KLD hydrogel only, or associated to growth factors. All control limbs received KLD hydrogel alone or received only trypsin but not hydrogel. Ninety days post-defect creation, the rabbits were euthanized and magnetic resonance imaging, radiography, macroscopic evaluation, histology, and immunohistochemistry of the joint and repaired tissue were performed. Mixed model analyses of variance were utilized to assess the outcome parameters and individual comparisons were performed using Least Square Means procedure and differences with p-value < 0.05 were considered significant. Trypsin enzymatic pre-treatment improved cellular morphology, cluster formation and subchondral bone reconstitution. Platelet-derived growth factor-BB improved subchondral bone healing and basal integration. Heparin-binding insulin-like growth factor-1 associated with platelet-derived growth factor improved tissue and cell morphology. The authors conclude that self-assembling KLD hydrogel functionalized with platelet-derived growth factor and heparin-binding insulin-like growth factor-1 with associated enzymatic pre-treatment of the native cartilage with trypsin resulted in an improvement on the cartilage repair process. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2307-2315, 2019., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Hormones with anabolic properties such as growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are commonly abused among professional and recreational athletes to enhance physical ability. Despite their adverse effects are well-documented, the use of GH and IGF-1 has recently grown. This article highlights the anabolic activity related to mechanisms of cancer development and progression. GH/IGF-1 axis is able to activate cellular mechanisms that modulate every key stage of cancer formation and progression, such as inhibition of apoptosis, resistance to treatments, and induction of angiogenesis, metastatic process and cell proliferation. Results from pre-clinical studies and epidemiological observations in patients with an excess of GH and IGF-1 production or treated with these hormones showed a positive association with the risk to develop several types of cancer. In conclusion, athletes should be made aware that long-term treatment with doping agents might increase the risk of developing cancer, especially if associated with other licit or illicit drugs and/or high-protein diet.

ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 (ST8SIA2) synthesizes polysialic acid (PSA), which is essential for brain development. Although previous studies reported that St8sia2-deficient mice that have a mixed 129 and C57BL/6 (B6) genetic background showed mild and variable phenotypes, the reasons for this remain unknown. We hypothesized that this phenotypic difference is caused by diversity in the expression or function of flanking genes of St8sia2. A genomic polymorphism and gene expression analysis in the flanking region revealed reduced expression of insulin-like growth factor 1 receptor (Igf1r) on the B6 background than on that of the 129 strain. This observation, along with the finding that administration of an IGF1R agonist during pregnancy increased litter size, suggests that the decreased expression of Igf1r associated with ST8SIA2 deficiency caused lethality. This study demonstrates the importance of gene expression level in the flanking regions of a targeted null allele having an effect on phenotype.

Microvascular muscle transfer is the gold standard for reanimation following chronic facial nerve paralysis, however, despite the regenerative capacity of peripheral motor axons, poor reinnervation often results in sub-optimal function. We hypothesized that injection of alginate hydrogels releasing growth factors directly into donor tissue would promote reinnervation, muscle regeneration, and function. A murine model of sciatic nerve ligation and neurorrhaphy was first used to assess the ability of gel delivery of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) to promote functional reinnervation. VEGF + IGF-1 gel delivery to aged mice resulted in prolonged ability to control toe movement, increased toe spreading, and improved static sciatic index score, indicative of improved sciatic nerve and neuromuscular junction function. Further, a 26% increase in muscle fiber area, and 2.8 and 3.0-fold increases in muscle contraction force and velocity, respectively, were found compared to blank alginate in the murine model. This strategy was subsequently tested in a rabbit model of craniofacial gracilis muscle transplantation. Electromyography demonstrated a 71% increase in compound muscle action potential 9 weeks after transplantation following treatment with VEGF + IGF-1 alginate, compared to blank alginate in the rabbit model. Improving functional innervation in transplanted muscle via a hydrogel source of growth factors may enhance the therapeutic outcomes of facial palsy treatments and, more broadly, muscle transplantations., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cancer mediated activation of the ActRIIB-ALK4/5 heterodimer by myostatin is strongly associated with muscle wasting. We investigated in vitro and in vivo the efficacy of ALK4/5 receptor blockers SB431542 and GW788388 in preventing muscle wasting, and explored synergy with IGF-I analogue LONG R3 (LR3) IGF-I. In vitro, C2C12 skeletal muscle cells were treated with vehicle, SB431542, GW788388 and LR3 IGF-I. A C26-CD2F1 cachexia model was used to induce cachexia in vivo. Mice were allocated as non-tumour bearing (NTB) or C26 tumour-bearing (C26 TB) vehicle control, treated with SB431542, LR3 IGF-I, SB431542 and LR3 IGF-I, or GW788388 (intraperitoneally or orally). In vitro, differentiation index and mean nuclei count increased using SB431542, GW788388, LR3 IGF-I. In vivo, GW788388 was superior to SB431542 in limiting loss of bodyweight, grip-strength and gastrocnemius weight. and downregulated Atrogin-1 expression comparable to NTB mice. LR3 IGF-I treatment limited loss of muscle mass, but at the expense of accelerated tumour growth. In conclusion, treatment with GW788388 prevented cancer cachexia, and downregulated associated ubiquitin ligase Atrogin-1.

Stem cell therapy in heart disease is challenged by mis-injection, poor survival, and low cell retention. Here, we describe a biocompatible multifunctional silica-iron oxide nanoparticle to help solve these issues. The nanoparticles were made via an in situ growth of Fe 3 O 4 nanoparticles on both the external surfaces and pore walls of mesocellular foam silica nanoparticles. In contrast to previous work, this approach builds a magnetic moiety inside the pores of a porous silica structure. These materials serve three roles: drug delivery, magnetic manipulation, and imaging. The addition of Fe 3 O 4 to the silica nanoparticles increased their colloidal stability, T 2 -based magnetic resonance imaging contrast, and superparamagnetism. We then used the hybrid materials as a sustained release vehicle of insulin-like growth factor-a pro-survival agent that can increase cell viability. In vivo rodent studies show that labeling stem cells with this nanoparticle increased the efficacy of stem cell therapy in a ligation/reperfusion model. The nanoparticle-labeled cells increase the mean left ventricular ejection fraction by 11 and 21% and the global longitudinal strain by 24 and 34% on days 30 and 60, respectively. In summary, this multifunctional nanomedicine improves stem cell survival via the sustained release of pro-survival agents.

Aim: The aim of this study was to evaluate the formulation of a synthetic IGF-1 (pIGF-1) in PLGA microparticles (MP). Methods: Poly (lactic-co-glycolic acid) (PLGA) MPs loaded with pIGF-1 were prepared, characterised and evaluated using double emulsion solvent evaporation method. Results: Spherical MPs showed an average particle size of 2 µm, encapsulation efficiency (EE) of 67% and 50% degradation over 15 days. With a view to enhancing retention in the myocardium, the MP formulation was encapsulated in a cross-linked hyaluronic acid hydrogel. pIGF-1 released from MPs and from MPs suspended in hyaluronic acid hydrogel remained bioactive, determined by a significant increase in cellular proliferation of c-kit + cells. Conclusion: This formulation has potential for loco-regional delivery to damaged myocardium to promote the survival of cardiomyocytes.