Preoperative factors associated with 180°, 270°, and 360° labral tears.

BACKGROUND: Large, circumferential glenoid labral tears are an uncommon injury affecting young, athletic patients. There are limited data describing the clinical presentation of patients with larger tears, especially 270° and 360° labral tears. Additionally, examination and imaging findings have poor reliability in diagnosing these tears. The purpose of this study was to determine the clinical presentation among patients presenting with small (less than 180°), medium (180°-270°), and large (270°-360°) labral tears. METHODS: This is a retrospective comparative study of consecutive patients surgically managed by a single shoulder surgeon for all glenoid labral tears from 2018-2022. The primary outcome was demographic and preoperative clinical risk factors. Demographic data including age, sex, hand dominance, body mass index, as well as clinical presentation (subluxation vs. dislocation, instability history, and participation in contact sports) were recorded. RESULTS: A total of 188 patients met the inclusion criteria: 101 of 188 (53.70%) patients with small tears, 43 of 188 (22.90%) patients with medium tears, and 44 of 188 (23.40%) patients with large tears. Individuals with large and medium-sized labral tears were more likely to have participated in contact sports compared to those with smaller labral tears (P = .003). Medium and smaller tears were more likely to present as dominant-side injury (P = .02). Furthermore, medium and large tears were more likely to present with anterior instability symptoms compared with smaller tears, which more frequently presented with posterior instability and pain (P = .003). CONCLUSION: Males participating in contact sports were the most common demographic population presenting with large, 270°-360° labral tears. Instability was the primary complaint rather than pain, and compared with small tears, medium and large tears were more likely to present with primary anterior instability. Although arthroscopic repair of 270°-360° labral tears can yield excellent clinical outcomes similar to smaller tears, identifying factors associated with larger glenoid labral tears may help in surgical planning and patient counseling.

Criteria-based return-to-sport testing helps identify functional deficits in young athletes following posterior labral repair but may not reduce recurrence or increase return to play.

Background: The purpose of this study was to compare recurrent instability and return to play (RTP) in young athletes who underwent clearance to full activity based on a validated return-to-sport (RTS) test to those who underwent time-based clearance following primary posterior labral repair. Methods: This was a retrospective review of athletes with posterior shoulder instability who underwent primary arthroscopic posterior labral repair from 2012 to 2021 with minimum 1-year follow-up. Patients who underwent RTS testing at a minimum of 5 months postoperatively were compared to a historic control cohort of patients who underwent time-based clearance. Results: There were 30 patients in the RTS cohort and 67 patients in the control cohort (mean follow-up 32.1 and 38.6 months, respectively). Of the 30 patients who underwent RTS testing, 11 passed without failing any sections, 10 passed while failing 1 section, and 9 failed the RTS test by failing 2+ sections. No differences were found between the RTS and control cohort in the incidence of recurrent instability (6.7% vs. 9.0%), overall RTP (94.7% vs. 94.3%), RTP at the same level as before injury (84.2% vs. 80.0%), recurrent pain/weakness (23.3% vs. 25.4%), or revision surgery (0% vs. 3.0%), respectively. Discussion: While RTS testing in young athletes after posterior labral repair did not reduce recurrence or improve return to play compared to time-based clearance, two-thirds of athletes who underwent testing failed at least 1 section, indicating some functional deficit. Thus, RTS testing may help guide postoperative rehabilitation following posterior stabilization.

Transient inhibition of meniscus cell migration following acute inflammatory challenge.

Meniscus tears represent a common orthopedic injury that often requires surgery to restore pain-free function. The need for surgical intervention is due, in part, to the inflammatory and catabolic environment that inhibits meniscus healing after injury. In other organ systems, healing is dependent on the migration of cells to the site of injury; however, in the meniscus, it is currently unknown how the microenvironment dictates cell migration in the postinjury inflamed setting. Here, we investigated how inflammatory cytokines alter meniscal fibrochondrocyte (MFC) migration and sensation of microenvironmental stiffness. We further tested whether an FDA approved interleukin-1 receptor antagonist (IL-1Ra; Anakinra) could rescue migratory deficits caused by inflammatory challenge. When cultured in the presence of inflammatory cytokines (tumor necrosis factor-α [TNF-α] or interleukin-1ß [IL-1ß]) for 1 day, MFC migration was inhibited for 3 days before returning to control levels at Day 7. This migratory deficit was clear in three-dimensional as well, where fewer MFCs exposed to inflammatory cytokines migrated from a living meniscal explant compared with control. Notably, addition of IL-1Ra to MFCs previously exposed to IL-1ß restored migration to baseline levels. This study demonstrates that joint inflammation can have negative impacts on meniscus cell migration and mechanosensation, affecting their potential for repair, and that resolution of this inflammation with concurrent anti-inflammatories can reverse these deficits. Future work will apply these findings to mitigate the negative consequences of joint inflammation and promote repair in a clinically relevant meniscus injury model.

Six-Month Outcomes of Clinically Relevant Meniscal Injury in a Large-Animal Model.

BACKGROUND: The corrective procedures for meniscal injury are dependent on tear type, severity, and location. Vertical longitudinal tears are common in young and active individuals, but their natural progression and impact on osteoarthritis (OA) development are not known. Root tears are challenging and they often indicate poor outcomes, although the timing and mechanisms of initiation of joint dysfunction are poorly understood, particularly in large-animal and human models. PURPOSE/HYPOTHESIS: In this study, vertical longitudinal and root tears were made in a large-animal model to determine the progression of joint-wide dysfunction. We hypothesized that OA onset and progression would depend on the extent of injury-based load disruption in the tissue, such that root tears would cause earlier and more severe changes to the joint. STUDY DESIGN: Controlled laboratory study. METHODS: Sham surgeries and procedures to create either vertical longitudinal or root tears were performed in juvenile Yucatan mini pigs through randomized and bilateral arthroscopic procedures. Animals were sacrificed at 1, 3, or 6 months after injury and assessed at the joint and tissue level for evidence of OA. Functional measures of joint load transfer, cartilage indentation mechanics, and meniscal tensile properties were performed, as well as histological evaluation of the cartilage, meniscus, and synovium. RESULTS: Outcomes suggested a progressive and sustained degeneration of the knee joint and meniscus after root tear, as evidenced by histological analysis of the cartilage and meniscus. This occurred in spite of spontaneous reattachment of the root, suggesting that this reattachment did not fully restore the function of the native attachment. In contrast, the vertical longitudinal tear did not cause significant changes to the joint, with only mild differences compared with sham surgery at the 6-month time point. CONCLUSION: Given that the root tear, which severs circumferential connectivity and load transfer, caused more intense OA compared with the circumferentially stable vertical longitudinal tear, our findings suggest that without timely and mechanically competent fixation, root tears may cause irreversible joint damage. CLINICAL RELEVANCE: More generally, this new model can serve as a test bed for experimental surgical, scaffold-based, and small molecule-driven interventions after injury to prevent OA progression.

The porcine accessory carpal bone as a model for biologic joint replacement for trapeziometacarpal osteoarthritis.

Given its complex shape and relatively small size, the trapezium surface at the trapeziometacarpal (TMC) joint is a particularly attractive target for anatomic biologic joint resurfacing, especially given its propensity to develop osteoarthritis, and the limited and sub-optimal treatment options available. For this to advance to clinical translation, however, an appropriate large animal model is required. In this study, we explored the porcine accessory carpal bone (ACB) as a model for the human trapezium. We characterized ACB anatomy, geometry, joint and tissue-scale mechanics, and composition across multiple donors. We showed that the ACB is similar both in size, and in the saddle shape of the main articulating surface to the human trapezium, and that loads experienced across each joint are similar. Using this information, we then devised a fabrication method and workflow to produce patient-specific tissue-engineered replicas based on CT scans, and showed that when such replicas are implanted orthotopically in an ex vivo model, normal loading is restored. Data from this study establish the porcine ACB as a model system in which to evaluate function of engineered living joint resurfacing strategies. STATEMENT OF SIGNIFICANCE: Biologic joint resurfacing, or the replacement of a joint with living tissue as opposed to metal and plastic, is the holy grail of orthopaedic tissue engineering. However, despite marked advances in engineering native-like osteochondral tissues and in matching patient-specific anatomy, these technologies have not yet reached clinical translation. Given its propensity for developing osteoarthritis, as well as its small size and complex shape, the trapezial surface of the trapeziometacarpal joint at the base of the thumb presents a unique opportunity for pursuing a biologic joint resurfacing strategy. This work establishes the porcine accessory carpal bone as an animal model for the human trapezium and presents a viable test-bed for evaluating the function of engineered living joint resurfacing strategies.

Stabilization of Damaged Articular Cartilage with Hydrogel-Mediated Reinforcement and Sealing.

Cartilage injuries and subsequent tissue deterioration impact millions of patients. Since the regeneration of functional hyaline cartilage remains elusive, methods to stabilize the remaining tissue, and prevent further deterioration, would be of significant clinical utility and prolong joint function. Finite element modeling shows that fortification of the degenerate cartilage (Reinforcement) and reestablishment of a superficial zone (Sealing) are both required to restore fluid pressurization within the tissue and restrict fluid flow and matrix loss from the defect surface. Here, a hyaluronic acid (HA) hydrogel system is designed to both interdigitate with and promote the sealing of the degenerated cartilage. Interdigitating fortification restores both bulk and local pericellular tissue mechanics, reestablishing the homeostatic mechanotransduction of endogenous chondrocytes within the tissue. This HA therapy is further functionalized to present chemo mechanical cues that improve the attachment and direct the response of mesenchymal stem/stromal cells at the defect site, guiding localized extracellular matrix deposition to "seal" the defect. Together, these results support the therapeutic potential, across cell and tissue length scales, of an innovative hydrogel therapy for the treatment of damaged cartilage.

Resorbable Pins to Enhance Scaffold Retention in a Porcine Chondral Defect Model.

OBJECTIVE: Cartilage repair strategies have seen improvement in recent years, especially with the use of scaffolds that serve as a template for cartilage formation. However, current fixation strategies are inconsistent with regards to retention, may be technically challenging, or may damage adjacent tissues or the implant itself. Therefore, the goal of this study was to evaluate the retention and repair potential of cartilage scaffolds fixed with an easy-to-implement bioresorbable pin. DESIGN: Electrospun hyaluronic acid scaffolds were implanted into trochlear groove defects in 3 juvenile and 3 adult pigs to evaluate short-term retention (2 weeks; pin fixation vs. press-fit and fibrin fixation) and long-term repair (8 months; scaffold vs. microfracture), respectively. RESULTS: For the retention study, press-fit and fibrin fixation resulted in short-term scaffold dislodgment (n = 2 each), whereas pin fixation retained all scaffolds that were implanted (n = 6). Pin fixation did not cause any damage to the opposing patellar surface, and only minor changes in the subchondral bone were observed. For long-term repair, no differences were observed between microfracture and scaffold groups, in terms of second-look arthroscopy and indentation testing. On closer visualization with micro computed tomography and histology, a high degree of variability was observed between animals with regard to subchondral bone changes and cartilage repair quality, yet each Scaffold repair displayed similar properties to its matched microfracture control. CONCLUSIONS: In this study, pin fixation did not cause adverse events in either the short- or the long-term relative to controls, indicating that pin fixation successfully retained scaffolds within defects without inhibiting repair.

Nuclear softening expedites interstitial cell migration in fibrous networks and dense connective tissues.

Dense matrices impede interstitial cell migration and subsequent repair. We hypothesized that nuclear stiffness is a limiting factor in migration and posited that repair could be expedited by transiently decreasing nuclear stiffness. To test this, we interrogated the interstitial migratory capacity of adult meniscal cells through dense fibrous networks and adult tissue before and after nuclear softening via the application of a histone deacetylase inhibitor, Trichostatin A (TSA) or knockdown of the filamentous nuclear protein Lamin A/C. Our results show that transient softening of the nucleus improves migration through microporous membranes, electrospun fibrous matrices, and tissue sections and that nuclear properties and cell function recover after treatment. We also showed that biomaterial delivery of TSA promoted in vivo cellularization of scaffolds by endogenous cells. By addressing the inherent limitations to repair imposed by nuclear stiffness, this work defines a new strategy to promote the repair of damaged dense connective tissues.

Transection of the medial meniscus anterior horn results in cartilage degeneration and meniscus remodeling in a large animal model.

The meniscus plays a central load-bearing role in the knee joint. Unfortunately, meniscus injury is common and can lead to joint degeneration and osteoarthritis (OA). In small animal models, progressive degenerative changes occur with the unloading of the meniscus via destabilization of the medial meniscus (DMM). However, few large animal models of DMM exist and the joint-wide initiation of the disease has not yet been defined in these models. Thus, the goal of this study is to develop and validate a large animal model of surgically induced DMM and to use multimodal (mechanical, histological, and magnetic resonance imaging) and multiscale (joint to tissue level) quantitative measures to evaluate degeneration in both the meniscus and cartilage. DMM was achieved using an arthroscopic approach in 13 Yucatan minipigs. One month after DMM, joint contact area decreased and peak pressure increased, indicating altered load transmission as a result of meniscus destabilization. By 3 months, the joint had adapted to the injury and load transmission patterns were restored to baseline, likely due to the formation and maturation of a fibrovascular scar at the anterior aspect of the meniscus. Despite this, we found a decrease in the indentation modulus of the tibial cartilage and an increase in cartilage histopathology scores at 1 month compared to sham-operated animals; these deleterious changes persisted through 3 months. Over this same time course, meniscus remodeling was evident through decreased proteoglycan staining in DMM compared to sham menisci at both 1 and 3 months. These findings support that arthroscopic DMM results in joint degeneration in the Yucatan minipig and provide a new large animal testbed in which to evaluate therapeutics and interventions to treat post-traumatic OA that originates from a meniscal injury.

Improved versus worsened endocrine function after transsphenoidal surgery for nonfunctional pituitary adenomas: rate, time course, and radiological analysis.

OBJECTIVE: The impact of transsphenoidal surgery for nonfunctional pituitary adenomas (NFAs) on preoperative hypopituitarism relative to the incidence of new postoperative endocrine deficits remains unclear. The authors investigated rates of hypopituitarism resolution and development after transsphenoidal surgery. METHODS: Over a 5-year period, 305 transsphenoidal surgeries for NFAs performed at The California Center for Pituitary Disorders were retrospectively reviewed. RESULTS: Patients with preoperative endocrine deficits (n = 153, 50%) were significantly older (mean age 60 vs 54 years; p = 0.004), more frequently male (65% vs 44%; p = 0.0005), and had larger adenomas (2.4 cm vs 2.1 cm; p = 0.02) than patients without preoperative deficits (n = 152, 50%). Of patients with preoperative endocrine deficits, 53% exhibited symptoms. Preoperative deficit rates were 26% for the thyroid axis; 20% and 16% for the male and female reproductive axes, respectively; 13% for the adrenocorticotropic hormone (ACTH)/cortisol axis, and 19% for the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Laboratory normalization rates 6 weeks and 6 months after surgery without hormone replacement were 26% and 36% for male and 13% and 13% for female reproductive axes, respectively; 30% and 49% for the thyroid axis; 3% and 3% for the cortisol axis; and 9% and 22% for the IGF-1 axis (p < 0.05). New postoperative endocrine deficits occurred in 42 patients (13.7%). Rates of new deficits by axes were: male reproductive 3% (n = 9), female reproductive 1% (n = 4), thyroid axis 3% (n = 10), cortisol axis 6% (n = 19), and GH/IGF-1 axis 4% (n = 12). Patients who failed to exhibit any endocrine normalization had lower preoperative gland volumes than those who did not (0.24 cm(3) vs 0.43 cm(3), respectively; p < 0.05). Multivariate analyses revealed that no variables predicted new postoperative deficits or normalization of the female reproductive, cortisol, and IGF-1 axes. However, increased preoperative gland volume and younger age predicted the chances of a patient with any preoperative deficit experiencing normalization of at least 1 axis. Younger age and less severe preoperative hormonal deficit predicted normalization of the thyroid and male reproductive axes (p < 0.05). CONCLUSIONS: After NFA resection, endocrine normalization rates in this study varied with the hormonal axis and were greater than the incidence of new endocrine deficits. Low preoperative gland volume precluded recovery. Patient age and the severity of the deficiency influenced the recovery of the thyroid and male reproductive axes, the most commonly impaired axes and most likely to normalize postoperatively. This information can be of use in counseling patients with hypopituitarism who undergo NFA surgery.

Incidence of headache as a presenting complaint in over 1000 patients with sellar lesions and factors predicting postoperative improvement.

INTRODUCTION: Due to the high incidence of headaches and pituitary tumors, neurosurgeons often evaluate patients with benign-appearing sellar lesions and headaches without insight into whether the headache is attributable to the lesion. We sought to evaluate the incidence of headache as a presenting complaint in patients undergoing transsphenoidal surgery for various pathologies and to identify factors predicting postoperative improvement. METHODS: We conducted a 5-year retrospective review of our first 1015 transsphenoidal surgeries since establishing a dedicated pituitary center. RESULTS: Of 1015 patients, 329 (32%) presented with headache. Of these 329 patients, 241 (73)% had headache as their chief complaint. Headache was most common in patients with apoplexy (84%), followed by Rathke's cleft cysts (RCCs) (60%). Multivariate analyses revealed diagnosis (P = 0.001), younger age (P = 0.001), and female gender (P = 0.006) to be associated with headache. Of patients presenting with headaches, 11% reported improvement at 6-week follow-up and 53% improved at 6-month follow-up. Multivariate analyses revealed gross total resection (GTR; P = 0.04) and decreased duration of headache (P = 0.04) to be associated with improvement, while diagnosis, age, gender, lesion size, whether headache was a chief complaint, and location of headache were not associated with improvement (P > 0.05). CONCLUSION: In analyzing over 1000 consecutive patients undergoing transsphenoidal surgery, younger patients, females, and patients with RCCs and apoplexy were more likely to present with headache. Patients who underwent GTR and had shorter duration of headache were more likely to experience headache improvement. This information can be used to counsel patients preoperatively.

Morbidity of repeat transsphenoidal surgery assessed in more than 1000 operations.

UNLABELLED: OBJECT.: While transsphenoidal surgery is associated with low morbidity, the degree to which morbidity increases after reoperation remains unclear. The authors determined the morbidity associated with repeat versus initial transsphenoidal surgery after 1015 consecutive operations. METHODS: The authors conducted a 5-year retrospective review of the first 916 patients undergoing transsphenoidal surgery at their institution after a pituitary center of expertise was established, and they analyzed morbidities. RESULTS: The authors analyzed 907 initial and 108 repeat transsphenoidal surgeries performed in 916 patients (9 initial surgeries performed outside the authors' center were excluded). The most common diagnoses were endocrine inactive (30%) or active (36%) adenomas, Rathke's cleft cysts (10%), and craniopharyngioma (3%). Morbidity of initial surgery versus reoperation included diabetes insipidus ([DI] 16% vs 26%; p = 0.03), postoperative hyponatremia (20% vs 16%; p = 0.3), new postoperative hypopituitarism (5% vs 8%; p = 0.3), CSF leak requiring repair (1% vs 4%; p = 0.04), meningitis (0.4% vs 3%; p = 0.02), and length of stay ([LOS] 2.8 vs 4.5 days; p = 0.006). Of intraoperative parameters and postoperative morbidities, 1) some (use of lumbar drain and new postoperative hypopituitarism) did not increase with second or subsequent reoperations (p = 0.3-0.9); 2) some (DI and meningitis) increased upon second surgery (p = 0.02-0.04) but did not continue to increase for subsequent reoperations (p = 0.3-0.9); 3) some (LOS) increased upon second surgery and increased again for subsequent reoperations (p < 0.001); and 4) some (postoperative hyponatremia and CSF leak requiring repair) did not increase upon second surgery (p = 0.3) but went on to increase upon subsequent reoperations (p = 0.001-0.02). Multivariate analysis revealed that operation number, but not sex, age, pathology, radiation therapy, or lesion size, increased the risk of CSF leak, meningitis, and increased LOS. Separate analysis of initial versus repeat transsphenoidal surgery on the 2 most common benign pituitary lesions, pituitary adenomas and Rathke's cleft cysts, revealed that the increased incidence of DI and CSF leak requiring repair seen when all pathologies were combined remained significant when analyzing only pituitary adenomas and Rathke's cleft cysts (DI, 13% vs 35% [p = 0.001]; and CSF leak, 0.3% vs 9% [p = 0.0009]). CONCLUSIONS: Repeat transsphenoidal surgery was associated with somewhat more frequent postoperative DI, meningitis, CSF leak requiring repair, and greater LOS than the low morbidity characterizing initial transsphenoidal surgery. These results provide a framework for neurosurgeons in discussing reoperation for pituitary disease with their patients.

Factors predicting postoperative hyponatremia and efficacy of hyponatremia management strategies after more than 1000 pituitary operations.

OBJECT: Syndrome of inappropriate antidiuretic hormone secretion-induced hyponatremia is a common morbidity after pituitary surgery that can be profoundly symptomatic and cause costly readmissions. The authors calculated the frequency of postoperative hyponatremia after 1045 consecutive operations and determined the efficacy of interventions correcting hyponatremia. METHODS: The authors performed a retrospective review of 1045 consecutive pituitary surgeries in the first 946 patients treated since forming a dedicated pituitary center 5 years ago. Patients underwent preoperative and daily inpatient sodium checks, with outpatient checks as needed. RESULTS: Thirty-two patients presented with hyponatremia; 41% of these patients were symptomatic. Postoperative hyponatremia occurred after 165 operations (16%) a mean of 4 days after surgery (range 0-28 days); 19% of operations leading to postoperative hyponatremia were associated with postoperative symptoms (38% involved dizziness and 29% involved nausea/vomiting) and 15% involved readmission for a mean of 5 days (range 1-20 days). In a multivariate analysis including lesion size, age, sex, number of prior pituitary surgeries, surgical approach, pathology, lesion location, and preoperative hypopituitarism, only preoperative hypopituitarism predicted postoperative hyponatremia (p = 0.006). Of patients with preoperative hyponatremia, 59% underwent medical correction preoperatively and 56% had persistent postoperative hyponatremia. The mean correction rates were 0.4 mEq/L/hr (no treatment; n = 112), 0.5 mEq/L/hr (free water restriction; n = 24), 0.7 mEq/L/hr (salt tablets; n = 14), 0.3 mEq/L/hr (3% saline; n = 20), 0.7 mEq/L/hr (intravenous vasopressin receptor antagonist Vaprisol; n = 22), and 1.2 mEq/L/hr (oral vasopressin receptor antagonist tolvaptan; n = 9) (p = 0.002, ANOVA). While some patients received more than 1 treatment, correction rates were only recorded when a treatment was given alone. CONCLUSIONS: After 1045 pituitary operations, postoperative hyponatremia was associated exclusively with preoperative hypopituitarism and was most efficiently managed with oral tolvaptan, with several interventions insignificantly different from no treatment. Promptly identifying hyponatremia in high-risk patients and management with agents like tolvaptan can improve safety and decrease readmission. For readmitted patients with severely symptomatic hyponatremia, the intravenous vasopressin receptor antagonist Vaprisol is another treatment option.

Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of antiangiogenic therapy resistance.

PURPOSE: To identify mediators of glioblastoma antiangiogenic therapy resistance and target these mediators in xenografts. EXPERIMENTAL DESIGN: We conducted microarray analysis comparing bevacizumab-resistant glioblastomas (BRG) with pretreatment tumors from the same patients. We established novel xenograft models of antiangiogenic therapy resistance to target candidate resistance mediator(s). RESULTS: BRG microarray analysis revealed upregulation versus pretreatment of receptor tyrosine kinase c-Met, which underwent further investigation because of its prior biologic plausibility as a bevacizumab resistance mediator. BRGs exhibited increased hypoxia versus pretreatment in a manner correlating with their c-Met upregulation, increased c-Met phosphorylation, and increased phosphorylation of c-Met-activated focal adhesion kinase and STAT3. We developed 2 novel xenograft models of antiangiogenic therapy resistance. In the first model, serial bevacizumab treatment of an initially responsive xenograft generated a xenograft with acquired bevacizumab resistance, which exhibited upregulated c-Met expression versus pretreatment. In the second model, a BRG-derived xenograft maintained refractoriness to the MRI tumor vasculature alterations and survival-promoting effects of bevacizumab. Growth of this BRG-derived xenograft was inhibited by a c-Met inhibitor. Transducing these xenograft cells with c-Met short hairpin RNA inhibited their invasion and survival in hypoxia, disrupted their mesenchymal morphology, and converted them from bevacizumab-resistant to bevacizumab-responsive. Engineering bevacizumab-responsive cells to express constitutively active c-Met caused these cells to form bevacizumab-resistant xenografts. CONCLUSION: These findings support the role of c-Met in survival in hypoxia and invasion, features associated with antiangiogenic therapy resistance, and growth and therapeutic resistance of xenografts resistant to antiangiogenic therapy. Therapeutically targeting c-Met could prevent or overcome antiangiogenic therapy resistance.

Roles of integrins in human induced pluripotent stem cell growth on Matrigel and vitronectin.

Human induced pluripotent stem cells (iPSCs) hold promise as a source of adult-derived, patient-specific pluripotent cells for use in cell-based regenerative therapies. However, current methods of cell culture are tedious and expensive, and the mechanisms underlying cell proliferation are not understood. In this study, we investigated expression and function of iPSC integrin extracellular matrix receptors to better understand the molecular mechanisms of cell adhesion, survival, and proliferation. We show that iPSC lines generated using Oct-3/4, Sox-2, Nanog, and Lin-28 express a repertoire of integrins similar to that of hESCs, with prominent expression of subunits alpha5, alpha6, alphav, beta1, and beta5. Integrin function was investigated in iPSCs cultured without feeder layers on Matrigel or vitronectin, in comparison to human embryonic stem cells. beta1 integrins were required for adhesion and proliferation on Matrigel, as shown by immunological blockade experiments. On vitronectin, the integrin alphavbeta5 was required for initial attachment, but inhibition of both alphavbeta5 and beta1 was required to significantly decrease iPSC proliferation. Furthermore, iPSCs cultured on vitronectin for 9 passages retained normal karyotype, pluripotency marker expression, and capacity to differentiate in vitro. These studies suggest that vitronectin, or derivatives thereof, might substitute for Matrigel in a more defined system for iPSC culture.