Cationic Polysaccharides Bind to the Endothelial Cell Surface Extracellular Matrix Involving Heparan Sulfate.

Cationic polysaccharides have been extensively studied for drug delivery via the bloodstream, yet few have progressed to clinical use. Endothelial cells lining the blood vessel wall are coated in an anionic extracellular matrix called the glycocalyx. However, we do not fully comprehend the charged polysaccharide interactions with the glycocalyx. We reveal that the cationic polysaccharide poly(acetyl, arginyl) glucosamine (PAAG) exhibits the highest association with the endothelial glycocalyx, followed by dextran (neutral) and hyaluronan (anionic). Furthermore, we demonstrate that PAAG binds heparan sulfate (HS) within the glycocalyx, leading to intracellular accumulation. Using an in vitro glycocalyx model, we demonstrate a charge-based extent of association of polysaccharides with HS. Mechanistically, we observe that PAAG binding to HS occurs via a condensation reaction and functionally protects HS from degradation. Together, this study reveals the interplay between polysaccharide charge properties and interactions with the endothelial cell glycocalyx toward improved delivery system design and application.

Wearable Accelerometer and Gyroscope Sensors for Estimating the Severity of Essential Tremor.

BACKGROUND: Several validated clinical scales measure the severity of essential tremor (ET). Their assessments are subjective and can depend on familiarity and training with scoring systems. METHOD: We propose a multi-modal sensing using a wearable inertial measurement unit for estimating scores on the Fahn-Tolosa-Marin tremor rating scale (FTM) and determine the classification accuracy within the tremor type. 17 ET participants and 18 healthy controls were recruited for the study. Two movement disorder neurologists who were blinded to prior clinical information viewed video recordings and scored the FTM. Participants drew a guided Archimedes spiral while wearing an inertial measurement unit placed at the mid-point between the lateral epicondyle of the humerus and the anatomical snuff box. Acceleration and gyroscope recordings were analyzed. The ratio of the power spectral density between frequency bands 0.5-4 Hz and 4-12 Hz, and the sum of power spectrum density over the entire spectrum of 2-74 Hz, for both accelerometer and gyroscope data, were computed. FTM was estimated using regression model and classification using SVM was validated using the leave-one-out method. RESULTS: Regression analysis showed a moderate to good correlation when individual features were used, while correlation was high ([Formula: see text] = 0.818) when suitable features of the gyro and accelerometer were combined. The accuracy for two-class classification of the combined features using SVM was 91.42% while for four-class it was 68.57%. CONCLUSION: Potential applications of this novel wearable sensing method using a wearable Inertial Measurement Unit (IMU) include monitoring of ET and clinical trials of new treatments for the disorder.

Assessing the diagnostic accuracy of CT perfusion: a systematic review.

Background and purpose: Computed tomography perfusion (CTP) has successfully extended the time window for reperfusion therapies in ischemic stroke. However, the published perfusion parameters and thresholds vary between studies. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines, we conducted a systematic review to investigate the accuracy of parameters and thresholds for identifying core and penumbra in adult stroke patients. Methods: We searched Medline, Embase, the Cochrane Library, and reference lists of manuscripts up to April 2022 using the following terms "computed tomography perfusion," "stroke," "infarct," and "penumbra." Studies were included if they reported perfusion thresholds and undertook co-registration of CTP to reference standards. The quality of studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool and Standards for Reporting of Diagnostic Accuracy (STARD) guidelines. Results: A total of 24 studies were included. A meta-analysis could not be performed due to insufficient data and significant heterogeneity in the study design. When reported, the mean age was 70.2 years (SD+/-3.69), and the median NIHSS on admission was 15 (IQR 13-17). The perfusion parameter identified for the core was relative cerebral blood flow (rCBF), with a median threshold of <30% (IQR 30, 40%). However, later studies reported lower thresholds in the early time window with rapid reperfusion (median 25%, IQR 20, 30%). A total of 15 studies defined a single threshold for all brain regions irrespective of collaterals and the gray and white matter. Conclusion: A single threshold and parameter may not always accurately differentiate penumbra from core and oligemia. Further refinement of parameters is needed in the current era of reperfusion therapy.

Using Semiology to Classify Epileptic Seizures vs Psychogenic Nonepileptic Seizures: A Meta-analysis.

Background and Objectives: A misdiagnosis of psychogenic nonepileptic seizures (PNES) and epileptic seizures (ES) is common. In the absence of the diagnostic gold standard (video EEG), clinicians rely on semiology and clinical assessment. However, questions regarding the diagnostic accuracy of different signs remain. This meta-analysis aimed to evaluate the diagnostic accuracy of semiology in PNES and ES. Methods: We systematically searched PubMed, PsycInfo, and Medline for original research publications published before 8 February 2021 with no restriction on search dates to identify studies that compared semiology in ES and PNES in epilepsy monitoring units. Non-English publications, review articles, studies reporting on only PNES or ES, and studies limited to patients with developmental delay were excluded. Study characteristics and proportions of event groups and patient groups demonstrating signs were extracted from each article. A bivariate analysis was conducted, and data were pooled in a random effects model for meta-analysis. The I 2 statistic was calculated to assess statistical heterogeneity. The revised Quality Assessment of Diagnostic Accuracy Studies tool was used to assess the risk of bias in included studies. The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were calculated. A PLR >10 or an NLR <0.1 largely affected the posttest probability of a diagnosis (ES or PNES), whereas a PLR between 5 and 10 or an NLR between 0.1 and 0.2 moderately affected the posttest probability of a diagnosis (ES or PNES). Results: The meta-analysis included 14 studies comprising 800 patients with ES and 452 patients with PNES. For PNES, ictal eye closure (PLR 40.5 95% confidence interval [CI] 16.2-101.3; I 2 = 0, from 3 studies) and asynchronous limb movements (PLR 10.2; 95% CI 2.8-37.7; I 2 = 0, from 3 studies) reached a PLR threshold >5. No single sign reached a PLR threshold >5 for ES. Discussion: While all signs require an interpretation in the overall clinical context, the presence of ictal eye closure and asynchronous limb movements are reliable discriminative signs for PNES.

Wearable sensors during drawing tasks to measure the severity of essential tremor.

Commonly used methods to assess the severity of essential tremor (ET) are based on clinical observation and lack objectivity. This study proposes the use of wearable accelerometer sensors for the quantitative assessment of ET. Acceleration data was recorded by inertial measurement unit (IMU) sensors during sketching of Archimedes spirals in 17 ET participants and 18 healthy controls. IMUs were placed at three points (dorsum of hand, posterior forearm, posterior upper arm) of each participant's dominant arm. Movement disorder neurologists who were blinded to clinical information scored ET patients on the Fahn-Tolosa-Marin rating scale (FTM) and conducted phenotyping according to the recent Consensus Statement on the Classification of Tremors. The ratio of power spectral density of acceleration data in 4-12 Hz to 0.5-4 Hz bands and the total duration of the action were inputs to a support vector machine that was trained to classify the ET subtype. Regression analysis was performed to determine the relationship of acceleration and temporal data with the FTM scores. The results show that the sensor located on the forearm had the best classification and regression results, with accuracy of 85.71% for binary classification of ET versus control. There was a moderate to good correlation (r2 = 0.561) between FTM and a combination of power spectral density ratio and task time. However, the system could not accurately differentiate ET phenotypes according to the Consensus classification scheme. Potential applications of machine-based assessment of ET using wearable sensors include clinical trials and remote monitoring of patients.

Computerised analysis of writing and drawing by essential tremor phenotype.

We investigated whether computerised analysis of writing and drawing could discriminate essential tremor (ET) phenotypes according to the 2018 Consensus Statement on the Classification of Tremors. The Consensus scheme emphasises soft additional findings, mainly motor, that do not suffice to diagnose another tremor syndrome. Ten men and nine women were classified by blinded assessors according to Consensus Axis 1 definitions of ET and ET plus. Blinded scoring of tremor severity and alternating limb movement was also conducted. Twenty healthy participants acted as controls. Four writing and three drawing tasks were performed on a Wacom Intuos Pro Large digital tablet with a pressure-sensor mounted ink pen. Sixty-seven computerised measurements were obtained, comprising static (dimensional and temporal), kinematic and pen pressure features. The mean age of ET participants was 67.2±13.0 years and mean tremor duration was 21.7±19.0 years. Six were classified as ET, five had one plus feature and eight had two plus features. The computerised analysis could predict the presence and number of ET plus features. Measures of acceleration and variation of pen pressure performed strongly to separate ET phenotypes (p<0.05). Plus features were associated with higher scores on the Fahn-Tolosa-Marin Tremor Rating Scale (p=0.001) and it appeared that ET groups were mainly being separated according to severity of tremor and by compensatory manoeuvres used by participants with more severe tremor. There were, in addition, a small number of negative kinematic correlations suggesting some slowness with ET plus. Abnormal repetitive limb movement was also correlated with tremor severity (R=0.57) by clinical grading. Critics of the Consensus Statement have drawn attention to weaknesses of the ET plus concept in relation to duration and severity of ET. This classification of ET may be too biased towards tremor severity to assist in distinguishing underlying biological differences by clinical measurement.

Raised visual contrast thresholds with intact attention and metacognition in functional motor disorder.

Functional motor disorders (FMDs) are distinguished by signs that lack congruence with recognised patterns of organic disease and show inconsistency over time. Their pathophysiology is poorly understood, but there is evidence that irregularities in perceptual and cognitive processing lie at the heart of these conditions. Here, we draw on a predictive coding account of functional neurological disorders to study perceptual decision-making in three groups: 20 patients with FMDs (14 with functional movements and 6 with functional weakness), 20 with phenotypically-matched organic motor disorders, and 20 age-matched healthy controls. We examine four cognitive domains with putative roles in FMD pathogenesis: attention, expectations, sensory processing (perceptual sensitivity), and metacognition (introspective evaluation of performance). We augmented a dual-task paradigm, manipulating the visual contrast required for target detection to examine these domains in one design. With sensory input (stimulus contrast) psychometrically adjusted to staircase target detection at a fixed level for all groups, the FMD group exhibited statistically equivalent attentional, expectational and metacognitive processing to healthy controls. However, we demonstrate Bayesian evidence and a frequentist trend that FMD patients require higher visual contrast than controls to maintain the same detection sensitivity (BF10 = 8.1, pholm = .066). This was statistically equivalent to the visual contrast required by the organic group, and unlikely to be accounted for by medication use or comorbid psychopathology. The organic group showed differences in processing of attention and expectations for target detection that were not observed in either healthy controls or the functional group. The distinctive behavioural profile of FMDs may arise from abnormalities in basic sensory processing, while higher attentional, expectational and metacognitive mechanisms remain intact. Conceptualising functional neurological disorders under a predictive coding account may consolidate and refine existing pathophysiological theories about them.

Human perivascular stem cell-derived extracellular vesicles mediate bone repair.

The vascular wall is a source of progenitor cells that are able to induce skeletal repair, primarily by paracrine mechanisms. Here, the paracrine role of extracellular vesicles (EVs) in bone healing was investigated. First, purified human perivascular stem cells (PSCs) were observed to induce mitogenic, pro-migratory, and pro-osteogenic effects on osteoprogenitor cells while in non-contact co-culture via elaboration of EVs. PSC-derived EVs shared mitogenic, pro-migratory, and pro-osteogenic properties of their parent cell. PSC-EV effects were dependent on surface-associated tetraspanins, as demonstrated by EV trypsinization, or neutralizing antibodies for CD9 or CD81. Moreover, shRNA knockdown in recipient cells demonstrated requirement for the CD9/CD81 binding partners IGSF8 and PTGFRN for EV bioactivity. Finally, PSC-EVs stimulated bone repair, and did so via stimulation of skeletal cell proliferation, migration, and osteodifferentiation. In sum, PSC-EVs mediate the same tissue repair effects of perivascular stem cells, and represent an 'off-the-shelf' alternative for bone tissue regeneration.

Cerebellar atrophy with Chiari malformation: An example of trans-synaptic degeneration?

A 23-year old man was found to have a Chiari Type 1 malformation and cerebellar atrophy. While this association has previously been described, the remote cerebellar atrophy is difficult to explain. We believe the answer lies with our finding of signal hyperintensity on MR imaging at the level of the inferior olives. This suggest hypertrophic olivary degeneration, caused by trans-synaptic degeneration following disruption to the Guillain-Mollaret triangle. Propagation of this process to the cerebellar Purkinje cells occurs in some cases. We describe a case in support of this hypothesis and review previously published evidence.

Comparison of Human Tissue Microarray to Human Pericyte Transcriptome Yields Novel Perivascular Cell Markers.

Human perivascular progenitor cells, including pericytes, are well-described multipotent mesenchymal cells giving rise to mesenchymal stem cells in culture. Despite the unique location of pericytes, specific antigens to distinguish human pericytes from other cell types are few. Here, we employed a human tissue microarray (Human Protein Atlas) to identify proteins that are strongly and specifically expressed in a pericytic location within human adipose tissue. Next, these results were cross-referenced with RNA sequencing data from human adipose tissue pericytes, as defined as a fluorescence activated cell sorting (FACS) purified CD146+CD34-CD31-CD45- cell population. Results showed that from 105,532 core biopsies of soft tissue, 229 proteins showed strong and specific perivascular immunoreactivity, the majority of which (155) were present in the tunica intima. Next, cross-referencing with the transcriptome of FACS-derived CD146+ pericytes yielded 25 consistently expressed genes/proteins, including 18 novel antigens. A majority of these transcripts showed maintained expression after culture propagation (56% of genes). Interestingly, many novel antigens within pericytes are regulators of osteogenic differentiation. In sum, our study demonstrates the existence of novel pericyte markers, some of which are conserved in culture that may be useful for future efforts to typify, isolate, and characterize human pericytes.

Heterotopic Ossification: A Comprehensive Review.

Heterotopic ossification (HO) is a diverse pathologic process, defined as the formation of extraskeletal bone in muscle and soft tissues. HO can be conceptualized as a tissue repair process gone awry and is a common complication of trauma and surgery. This comprehensive review seeks to synthesize the clinical, pathoetiologic, and basic biologic features of HO, including nongenetic and genetic forms. First, the clinical features, radiographic appearance, histopathologic diagnosis, and current methods of treatment are discussed. Next, current concepts regarding the mechanistic bases for HO are discussed, including the putative cell types responsible for HO formation, the inflammatory milieu and other prerequisite "niche" factors for HO initiation and propagation, and currently available animal models for the study of HO of this common and potentially devastating condition. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Skeletogenic Capacity of Human Perivascular Stem Cells Obtained Via Magnetic-Activated Cell Sorting.

Human perivascular stem/stromal cells (PSC) are a multipotent mesenchymal progenitor cell population defined by their perivascular residence. PSC are increasingly studied for their application in skeletal regenerative medicine. PSC from subcutaneous white adipose tissue are most commonly isolated via fluorescence-activated cell sorting (FACS), and defined as a bipartite population of CD146+CD34-CD31-CD45- pericytes and CD34+CD146-CD31-CD45- adventitial cells. FACS poses several challenges for clinical translation, including requirements for facilities, equipment, and personnel. The purpose of this study is to identify if magnetic-activated cell sorting (MACS) is a feasible method to derive PSC, and to determine if MACS-derived PSC are comparable to our previous experience with FACS-derived PSC. In brief, CD146+ pericytes and CD34+ adventitial cells were enriched from human lipoaspirate using a multistep column approach. Next, cell identity and purity were analyzed by flow cytometry. In vitro multilineage differentiation studies were performed with MACS-defined PSC subsets. Finally, in vivo application was performed in nonhealing calvarial bone defects in Scid mice. Results showed that human CD146+ pericytes and CD34+ adventitial cells may be enriched by MACS, with defined purity, anticipated cell surface marker expression, and capacity for multilineage differentiation. In vivo, MACS-derived PSC induce ossification of bone defects. These data document the feasibility of a MACS approach for the enrichment and application of PSC in the field of tissue engineering and regenerative medicine. Impact Statement Our findings suggest that perivascular stem/stromal cells, and in particular adventitial cells, may be isolated by magnetic-activated cell sorting and applied as an uncultured autologous stem cell therapy in a same-day setting for bone defect repair.

Overlapping features of rapidly progressive osteoarthrosis and Charcot arthropathy.

Nerve growth factor (NGF) is the primary neurotrophin in the skeleton and a central mediator of skeletal pain. Recent trials of anti-NGF neutralizing antibodies have resulted in infrequent but well-described incidence of rapidly progressive osteoarthrosis (RPOA). Neuropathy, whether from syphilis or diabetes, is also associated with severe joint destruction, known as neuroarthropathy or Charcot joint. These commonalities of severe joint destruction with either loss of a neurotrophin (anti-NGF) or a deficit of functional skeletal innervation led us to examine our institutional case files for potential radio-pathologic overlap between RPOA and Charcot joint.

Age dependent effects of NELL-1 isoforms on bone marrow stromal cells.

NELL-1 is an osteogenic protein first discovered to control ossification of the cranium. NELL-1 exists in at least two isoforms. The full-length NELL-1 contains 810 amino acid (aa) (NELL-1810), the N-terminal-truncated NELL-1 isoform contains 570 aa (NELL-1570). The differences in cellular effects between NELL-1 isoforms are not well understood. Methods: Here, BMSC were derived from adult or aged mice, followed by overexpression of NELL-1810 or NELL-1570. Cell morphology, proliferation, and gene expression were examined. Results/Conclusions: Overall, the proliferative effect of NELL-1570 was age dependent, showing prominent induction in adult but not aged mice.

Inferring the long duration response to levodopa in Parkinson's disease.

INTRODUCTION: The long duration response to levodopa in Parkinson's disease outlasts drug elimination by days to weeks. Though a substantive part of anti-parkinsonian motor benefit, it cannot easily be observed. OBJECTIVES: To infer the magnitude of the long duration response during the first decade of Parkinson's disease and identify factors that influence it. METHODS: Serial practically defined off scores of 24 patients from a longitudinal study of levodopa short duration response were used to establish their rate of motor progression. A line of notional untreated disability (as if drug treatment had never been given) with the same progression gradient was the basis for calculation of the long duration response. Predictors of mean long duration response amplitude were identified using a multiple linear regression model. RESULTS: Over a mean treatment period of 16.6 ±â€¯4.4 years, annual increase in motor disability was 2.3% of the maximum score. The long duration response composed 49% of total levodopa response during the first decade of treatment, and this proportion was significantly higher soon after commencing levodopa (p = 0.001). Higher pre-treatment motor score (r = 0.60) and lower MMSE (r = 0.60) were the main predictors of a larger long duration response. There was little correlation between long and short duration responses. CONCLUSIONS: Long duration responses contribute almost half of the total levodopa benefit during the first decade of treatment. An appreciation of both long and short duration components of drug symptomatic effects is important in clinical trial design to investigate possible neuroprotective treatments.

WISP-1 drives bone formation at the expense of fat formation in human perivascular stem cells.

The vascular wall within adipose tissue is a source of mesenchymal progenitors, referred to as perivascular stem/stromal cells (PSC). PSC are isolated via fluorescence activated cell sorting (FACS), and defined as a bipartite population of pericytes and adventitial progenitor cells (APCs). Those factors that promote the differentiation of PSC into bone or fat cell types are not well understood. Here, we observed high expression of WISP-1 among human PSC in vivo, after purification, and upon transplantation in a bone defect. Next, modulation of WISP-1 expression was performed, using WISP-1 overexpression, WISP-1 protein, or WISP-1 siRNA. Results demonstrated that WISP-1 is expressed in the perivascular niche, and high expression is maintained after purification of PSC, and upon transplantation in a bone microenvironment. In vitro studies demonstrate that WISP-1 has pro-osteogenic/anti-adipocytic effects in human PSC, and that regulation of BMP signaling activity may underlie these effects. In summary, our results demonstrate the importance of the matricellular protein WISP-1 in regulation of the differentiation of human stem cell types within the perivascular niche. WISP-1 signaling upregulation may be of future benefit in cell therapy mediated bone tissue engineering, for the healing of bone defects or other orthopaedic applications.

Deep Brain Stimulation for Parkinson's disease changes perception in the Rubber Hand Illusion.

Parkinson's disease (PD) alters cortico-basal ganglia-thalamic circuitry and susceptibility to an illusion of bodily awareness, the Rubber Hand Illusion (RHI). Bodily awareness is thought to result from multisensory integration in a predominantly cortical network; the role of subcortical connections is unknown. We studied the effect of modulating cortico-subcortical circuitry on multisensory integration for bodily awareness in 24 PD patients treated with subthalamic nucleus (STN) deep brain stimulation (DBS), in comparison to 21 healthy volunteers, using the RHI experiment. Typically, synchronous visuo-tactile cues induce a false perception of touch on the rubber hand as if it were the subject's hand, whereas asynchronous visuo-tactile cues do not. However, we found that in the asynchronous condition, patients in the off-stimulation state did not reject the RHI as strongly as healthy controls; patients' rejection of the RHI strengthened when STN-DBS was switched on, although it remained weaker than that of controls. Patients in the off-stimulation state also misjudged the position of their hand, indicating it to be closer to the rubber hand than controls. However, STN-DBS did not affect proprioceptive judgements or subsequent arm movements altered by the perceptual effects of the illusion. Our findings support the idea that the STN and subcortical connections have a key role in multisensory integration for bodily awareness. Decision-making in multisensory bodily illusions is discussed.

Frontal Bone Healing Is Sensitive to Wnt Signaling Inhibition via Lentiviral-Encoded Beta-Catenin Short Hairpin RNA.

The Wnt/ß-catenin signaling pathway plays an integral role in skeletal biology, spanning from embryonic skeletal patterning through bone maintenance and bone repair. Most experimental methods to antagonize Wnt signaling in vivo are either systemic or transient, including genetic approaches, use of small-molecule inhibitors, or neutralizing antibodies. We sought to develop a novel, localized model of prolonged Wnt/ß-catenin signaling blockade by the application and validation of a lentivirus encoding ß-catenin short hairpin RNA (shRNA). Efficacy of lentiviral-encoded ß-catenin shRNA was first confirmed in vitro using bone marrow mesenchymal stromal cells, and in vivo using an intramedullary long bone injection model in NOD SCID mice. Next, the effects of ß-catenin knockdown were assessed in a calvarial bone defect model, in which the frontal bone demonstrates enhanced bone healing associated with heightened Wnt/ß-catenin signaling. Lentivirus encoding either ß-catenin shRNA or random sequence shRNA with enhanced green fluorescent protein (control) was injected overlying the calvaria of NOD SCID mice and bone defects were created in either the frontal or parietal bones. Among mice treated with lentivirus encoding ß-catenin shRNA, frontal bone defect healing was significantly reduced by all radiographic and histologic metrics. In contrast, parietal bone healing was minimally impacted by ß-catenin shRNA. In aggregate, our data document the application and validation of a lentivirus encoding ß-catenin shRNA model that represents an easily replicable tool for examining the importance of locoregional Wnt/ß-catenin signaling in bone biology and regeneration.

Effects of WNT3A and WNT16 on the Osteogenic and Adipogenic Differentiation of Perivascular Stem/Stromal Cells.

Human perivascular stem/stromal cells (hPSC) are a multipotent mesenchymogenic stromal cell population defined by their perivascular locale. Recent studies have demonstrated the high potential for clinical translation of this fluorescence-activated cell sorting (FACS)-derived cell population for autologous bone tissue engineering. However, the mechanisms underlying the osteogenic differentiation of PSC are incompletely understood. The current study investigates the roles of canonical and noncanonical Wnt signaling in the osteogenic and adipogenic differentiation of PSC. Results showed that both canonical and noncanonical Wnt signaling activity transiently increased during PSC osteogenic differentiation in vitro. Sustained WNT3A treatment significantly decreased PSC osteogenic differentiation. Conversely, sustained treatment with Wnt family member 16 (WNT16), a mixed canonical and noncanonical ligand, increased osteogenic differentiation in a c-Jun N-terminal kinase (JNK) pathway-dependent manner. Conversely, WNT16 knockdown significantly diminished PSC osteogenic differentiation. Finally, WNT16 but not WNT3A increased the adipogenic differentiation of PSC. These results indicate the importance of regulation of canonical and noncanonical Wnt signaling for PSC fate and differentiation. Moreover, these data suggest that WNT16 plays a functional and necessary role in PSC osteogenesis.

Early Immunomodulatory Effects of Implanted Human Perivascular Stromal Cells During Bone Formation.

Human perivascular stem/stromal cells (PSC) are a multipotent mesodermal progenitor cell population defined by their perivascular residence. PSC are most commonly derived from subcutaneous adipose tissue, and recent studies have demonstrated the high potential for clinical translation of this fluorescence-activated cell sorting-derived cell population for bone tissue engineering. Specifically, purified PSC induce greater bone formation than unpurified stroma taken from the same patient sample. In this study, we examined the differences in early innate immune response to human PSC or unpurified stroma (stromal vascular fraction [SVF]) during the in vivo process of bone formation. Briefly, SVF or PSC from the same patient sample were implanted intramuscularly in the hindlimb of severe combined immunodeficient (SCID) mice using an osteoinductive demineralized bone matrix carrier. Histological examination of early inflammatory infiltrates was examined by hematoxylin and eosin and immunohistochemical staining (Ly-6G, F4/80). Results showed significantly greater neutrophilic and macrophage infiltrates within and around SVF in comparison to PSC-laden implants. Differences in early postoperative inflammation among SVF-laden implants were associated with reduced osteogenic differentiation and bone formation. Similar findings were recapitulated with PSC implantation in immunocompetent mice. Exaggerated postoperative inflammation was associated with increased IL-1α, IL-1ß, IFN-γ, and TNF-α gene expression among SVF samples, and conversely increased IL-6 and IL-10 expression among PSC samples. These data document a robust immunomodulatory effect of implanted PSC, and an inverse correlation between host inflammatory cell infiltration and stromal progenitor cell-mediated ossification.