Adipose tissue is an attractive source of mesenchymal stem cells (MSCs) because of its abundance and accessibility. We have previously defined a population of native MSCs termed perivascular stem cells (PSCs), purified from diverse human tissues, including adipose tissue. Human PSCs (hPSCs) are a bipartite cell population composed of pericytes (CD146+CD34-CD45-) and adventitial cells (CD146-CD34+CD45-), isolated by fluorescence-activated cell sorting and with properties identical to those of culture identified MSCs. Our previous studies showed that hPSCs exhibit improved bone formation compared with a sample-matched unpurified population (termed stromal vascular fraction); however, it is not known whether hPSCs would be efficacious in a spinal fusion model. To investigate, we evaluated the osteogenic potential of freshly sorted hPSCs without culture expansion and differentiation in a rat model of posterolateral lumbar spinal fusion. We compared increasing dosages of implanted hPSCs to assess for dose-dependent efficacy. All hPSC treatment groups induced successful spinal fusion, assessed by manual palpation and microcomputed tomography. Computerized biomechanical simulation (finite element analysis) further demonstrated bone fusion with hPSC treatment. Histological analyses showed robust endochondral ossification in hPSC-treated samples. Finally, we confirmed that implanted hPSCs indeed differentiated into osteoblasts and osteocytes; however, the majority of the new bone formation was of host origin. These results suggest that implanted hPSCs positively regulate bone formation via direct and paracrine mechanisms. In summary, hPSCs are a readily available MSC population that effectively forms bone without requirements for culture or predifferentiation. Thus, hPSC-based products show promise for future efforts in clinical bone regeneration and repair.
Adipose tissue is an attractive source of mesenchymal stem cells (MSCs) because of its abundance and accessibility. We have previously defined a population of native MSCs termed perivascular stem cells (PSCs), purified from diverse human tissues, including adipose tissue. Human PSCs (hPSCs) are a bipartite cell population composed of pericytes (CD146+CD342CD452) and adventitial cells (CD1462CD34+ CD452), isolated by fluorescence-activated cell sorting and with properties identical to those of culture identified MSCs. Our previous studies showed that hPSCs exhibit improved bone formation compared with a sample-matched unpurified population (termed stromal vascular fraction); however, it is not known whether hPSCs would be efficacious in a spinal fusion model. To investigate, we evaluated the osteogenic potential of freshly sorted hPSCs without culture expansion and differentiation in a rat model of posterolateral lumbar spinal fusion. We compared increasing dosages of implanted hPSCs to assess for dose-dependent efficacy. All hPSC treatment groups induced successful spinal fusion, assessed by manual palpation and microcomputed tomography. Computerized biomechanical simulation (finite element analysis) further demonstrated bone fusion with hPSC treatment. Histological analyses showed robust endochondral ossification in hPSC-treated samples. Finally, we confirmed that implanted hPSCs indeed differentiated into osteoblasts and osteocytes; however, the majority of the new bone formation was of host origin. These results suggest that implanted hPSCs positively regulate bone formation via direct and paracrine mechanisms. In summary, hPSCs are a readily available MSC population that effectively forms bone without requirements for culture or predifferentiation. Thus, hPSC-based products show promise for future efforts in clinical bone regeneration and repair. STEM CELLS
Hemodynamic responses to cocaine vary greatly between animals, and the variability is related to the incidence of cocaine-induced cardiomyopathies and hypertension. The variability in cardiac output and systemic vascular resistance responses to cocaine in individuals is correlated with the responses to acute startle (air jet). This experiment was designed to determine whether responses to cocaine and to air jet are related to those evoked by a conditioned stimulus (tone preceding foot shock) and to an unconditioned stimulus (cold water). We verified the relationship in hemodynamic response patterns between cocaine and cold stress using selective receptor antagonists. Rats were instrumented with a pulsed Doppler flow probe on the ascending aorta for determination of cardiac output and with an arterial cannula for recording arterial pressure and heart rate. After recovery, some rats were tested multiple times with four different stimuli: air jet (6 trials), 15-s tone preceding 1-s foot shock (12 trials), cold water exposure (1 cm deep for 1 min, 4-12 trials), and cocaine (5 mg/kg iv, 4-6 trials) while hemodynamic parameters were recorded. Each stimulus was capable of eliciting a pressor response that was associated with variable changes in cardiac output. The cardiac output response to cocaine was correlated with the initial responses to each stressor in individual rats. Responses evoked by cold stress were most similar to those elicited by cocaine. Furthermore, nicardipine (25 microg/kg iv) or atropine methylbromide (0.5 mg/kg iv) pretreatment prevented the cardiac output differences to acute cold stress, as noted after cocaine administration. On the other hand, propranolol (1 mg/kg iv) exacerbated both the decrease in cardiac output and the stress-induced increase in systemic vascular resistance as previously reported with cocaine. Therefore, the initial response to cold water exposure is a reliable method of evoking characteristic hemodynamic response patterns that, as seen with cocaine, may provide a suitable model for identifying the causes for predilection to stress-induced cardiovascular disease.
Cocaine or air jet stress evokes pressor responses due to either a large increase in systemic vascular resistance (vascular responders) or small increases in both cardiac output and vascular resistance (mixed responders) in conscious rats. Repeated cocaine administration results in elevated arterial pressure in vascular responders but not in mixed responders. The present study examined the hypothesis that the pattern of cardiovascular responses to an unconditioned stimulus (UCS; air jet) is related to responses to a conditioned stimulus (CS; tone followed by brief foot shock) in individual rats. Our data demonstrate that presentation of the UCS produced variable cardiac output responses that correlated with responses to the CS (n = 60). We also determined whether individual cardiovascular response patterns to acute stress correlated with predisposition to a sustained stress-induced elevation in arterial pressure. Rats were exposed to three different stressors presented one per day successively for 4 wk and during a poststress period of 3 wk while arterial pressure was recorded periodically. Mean arterial pressure was elevated in all rats during chronic stress but, during the poststress period, remained at significantly higher levels in vascular responders but not mixed responders. Therefore, we conclude that acute behavioral stress to a conditioned stimulus elicits variable hemodynamic responses that predict the predisposition to a sustained stress-induced elevation in arterial pressure.
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