Citations

Objective Bone marrow aspiration and concentration (BMAC) is becoming a more common regenerative therapy for musculoskeletal pathology. In our current pilot study, we studied patients with mild-to-moderate bilateral knee osteoarthritis, compared pain at 12-month follow-up between BMAC-injected and saline-injected knees, and examined cartilage appearance measured by magnetic resonance imaging (MRI) T2 quantitative mapping. Design Twenty-five patients with mild-to-moderate bilateral osteoarthritic knee pain were randomized to receive BMAC into one knee and saline placebo into the other. Bone marrow was aspirated from the iliac crests, concentrated in an automated centrifuge, combined with platelet-poor plasma for knee injection, and compared with saline injection into the contralateral knee. Primary outcome measures were T2 MRI cartilage mapping at 6-month and Visual Analog Scale and Osteoarthritis Research Society International Intermittent and Constant Osteoarthritis Pain scores and radiographs at 12-month follow-up. Results Constant, intermittent, and overall knee pain remained significantly decreased from baseline at 12-month follow-up (all P ⩽ 0.01), with no apparent difference between BMAC- and saline-treated knees (all P ⩾ 0.54). A similar significant increase from baseline to 12-month follow-up regarding quality of life was observed for both BMAC- and saline-treated knees (all P ⩽ 0.04). T2 quantitative MRI mapping showed no significant changes as a result of treatment. Conclusions BMAC is safe to perform and relieves pain from knee arthritis but showed no superiority to saline injection at 12-month follow-up. MRI cartilage sequences failed to show regenerative benefit with single BMAC injection. The mechanisms of action that led to pain relief remain unclear and warrant further studies.

BACKGROUNDClinical trials involving mesenchymal stem cell (MSC) therapy have variable outcomes. We hypothesize this is largely attributed to donor‐to‐donor variability and tissue of origin.STUDY DESIGN AND METHODSWe examined proliferation rates, cytokine secretion profiles, and differentiation capability of seven bone marrow–derived MSCs (BM‐MSCs) and 16 adipose tissue–derived MSCs (AD‐MSCs) from 23 donors.RESULTSAD‐MSCs had the capacity to undergo more than 40 population doublings, while the BM‐MSC proliferation rate was found to be considerably slower. We observed more donor‐to‐donor variability in proliferation rates of BM‐MSCs than with AD‐MSCs. Cytokine analysis revealed that secretion of eight cytokines was significantly increased by AD‐MSCs at Passage (P)3 compared with P1, while for BM‐MSCs at P3 relative to P1, only interleukin‐8 and RANTES secretion was significantly increased. By P5, secretion of all cytokines by AD‐MSCs was either decreased or unchanged relative to P1. In contrast, cytokine secretion by BM‐MSCs at P5 was mostly unchanged, although secretion of six cytokines was significantly increased relative to P1. When we compared cytokine secretion between AD‐MSCs and BM‐MSCs at P3, AD‐MSCs significantly secreted higher concentrations of cytokines than BM‐MSCs while the opposite was observed at P5. This suggests that BM‐MSCs are relatively more potent at P5 while AD‐MSCs are relatively more potent at P3. AD‐MSCs and BM‐MSCs exhibited the capacity for chondrogenic differentiation. AD‐MSCs and BM‐MSCs appeared to display a more enhanced inclination toward adipogenic and osteogenic differentiation, respectively.CONCLUSIONMSC physiology is significantly influenced by donor variability and tissue of origin and this should be considered when designing clinical trials.

BACKGROUND: There has been a surge in clinical trials studying the safety and efficacy of mesenchymal stem cells for the treatment of perianal Crohn’s disease. OBJECTIVE: The purpose of this work was to systematically review the literature to determine safety and efficacy of mesenchymal stem cells for the treatment of refractory perianal Crohn’s disease. DATA SOURCES: Sources included PubMed, Cochrane Library Central Register of Controlled Trials, and Embase. STUDY SELECTION: Studies that reported safety and/or efficacy of mesenchymal stem cells for the treatment of perianal Crohn’s disease were included. Two independent assessors reviewed eligible articles. INTERVENTION: The study intervention was delivery of mesenchymal stem cells to treat perianal Crohn’s disease. MAIN OUTCOMES MEASURES: Safety and efficacy of mesenchymal stem cells used to treat perianal Crohn’s disease were measured. RESULTS: Eleven studies met the inclusion criteria and were included in the systematic review. Three trials with a comparison arm were included in the meta-analysis. There were no significant increases in adverse events (OR = 1.07 (95% CI, 0.61–1.89); p = 0.81) or serious adverse events (OR = 0.53 (95% CI, 0.28–0.98); p = 0.04) in patients treated with mesenchymal stem cells. Mesenchymal stem cells were associated with improved healing as compared with control subjects at primary end points of 6 to 24 weeks (OR = 3.06 (95% CI, 1.05–8.90); p = 0.04) and 24 to 52 weeks (OR = 2.37 (95% CI, 0.90–6.25); p = 0.08). LIMITATIONS: The study was limited by its multiple centers and heterogeneity in the study inclusion criteria, mesenchymal stem cell origin, dose and frequency of delivery, use of scaffolding, and definition and time point of fistula healing. CONCLUSIONS: Although there have been only 3 trials conducted with control arms, existing data demonstrate improved efficacy and no increase in adverse or serious adverse events with mesenchymal stem cells as compared with control subjects for the treatment of perianal Crohn’s disease.

Abstract Feasibility, tolerance, and safety of intravenous infusions of allogeneic mesenchymal stem cell (MSC) therapy in lung transplant recipients with bronchiolitis obliterans syndrome (BOS) are not well established. MSCs were manufactured, cryopreserved, transported to our facility, thawed, and infused into nine recipients with moderate BOS (average drop in forced expiratory volume in 1 second was 56.8% ± 3.2% from post-transplant peak) who were refractory to standard therapy and not candidates for retransplant. Cells were viable and sterile prior to infusion. Patients received a single infusion of either 1 (n = 3), 2 (n = 3), or 4 (n = 3) million MSCs per kg. Patients were medically evaluated before; during; and at 24 hours, 1 week, and 1 month after infusion for evidence of infusion-related adverse events and tolerance of therapy. Vital signs, pulmonary function test results, Borg Dyspnea Index, and routine laboratory data were recorded. Vital signs and O2 saturation did not significantly change during or up to 2 hours after MSC infusion. There were no significant changes in gas exchange variables, pulmonary function test results, or laboratory values at 1, 7, and 30 days postinfusion compared with preinfusion values. Infusion of MSCs in patients with BOS was feasible, safe, and well tolerated and did not produce any significant adverse changes in clinical, functional, or laboratory variables during or up to 30 days after infusion. Manufacturing, transport, and administration of intravenous, allogeneic bone marrow-derived MSCs in doses from 1 to 4 million MSCs per kg is safe in lung transplant recipients with BOS.

Background: Bone marrow aspirate concentrate (BMAC) is increasingly used as a regenerative therapy for musculoskeletal pathological conditions despite limited evidence-based support. Hypothesis: BMAC will prove feasible, safe, and efficacious for the treatment of pain due to mild to moderate degenerative joint disease of the knee. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: In this prospective, single-blind, placebo-controlled trial, 25 patients with bilateral knee pain from bilateral osteoarthritis were randomized to receive BMAC into one knee and saline placebo into the other. Fifty-two milliliters of bone marrow was aspirated from the iliac crests and concentrated in an automated centrifuge. The resulting BMAC was combined with platelet-poor plasma for an injection into the arthritic knee and was compared with a saline injection into the contralateral knee, thereby utilizing each patient as his or her own control. Safety outcomes, pain relief, and function as measured by Osteoarthritis Research Society International (OARSI) measures and the visual analog scale (VAS) score were tracked initially at 1 week, 3 months, and 6 months after the procedure. Results: There were no serious adverse events from the BMAC procedure. OARSI Intermittent and Constant Osteoarthritis Pain and VAS pain scores in both knees decreased significantly from baseline at 1 week, 3 months, and 6 months ( P ≤ .019 for all). Pain relief, although dramatic, did not differ significantly between treated knees ( P > .09 for all). Conclusion: Early results show that BMAC is safe to use and is a reliable and viable cellular product. Study patients experienced a similar relief of pain in both BMAC- and saline-treated arthritic knees. Further study is required to determine the mechanisms of action, duration of efficacy, optimal frequency of treatments, and regenerative potential. Registration: ClinicalTrials.gov record 12-004459.

BACKGROUNDUmbilical cord blood (UCB) units collected from African Americans (AAs) have lower total nucleated cell (TNC) and CD34+ cell counts and are more likely to disqualify for banking compared to other ethnic groups. Furthermore, AAs have higher prevalence of 25‐hydroxyvitamin D (25(OH)D) deficiency. Given the importance of 25(OH)D in hematopoiesis, we examined the racial differences in UCB unit 25(OH)D content and its correlation with UCB cellular characteristics.STUDY DESIGN AND METHODSA total of 119 UCB units that did not meet the TNC count banking criteria were analyzed. Fifty‐one UCB units were collected from AA mothers and 68 from Caucasian mothers. We analyzed UCB volume, hematocrit (Hct), TNCs, mononuclear cells (MNCs), CD34+ cells, plasma 25(OH)D concentration, and progenitor clonogenic capacity measured by colony‐forming cell (CFC) assay.RESULTSCompared to Caucasians, AAs had significantly lower UCB 25(OH)D levels (p < 0.0001), TNCs (p = 0.002), MNCs (p = 0.026), and CD34+ cells (p = 0.026). Severe deficiency (25(OH)D < 10 ng/mL) was only detected in AAs. No difference in median CFC count/10,000 MNCs was detected between AAs and Caucasians. Independent of race, a significant association was detected between 25(OH)D level and TNCs (r = 0.193 p = 0.035) and Hct (r = 0.196 p = 0.033).CONCLUSIONThese results indicate the importance of 25(OH)D level as a racially independent predictor of UCB cellular characteristics and support further investigation of bioactive vitamin D and other predictors of hematopoiesis on cord blood quality.

BACKGROUNDPoor marrow cellularity alone cannot explain poor hematopoietic progenitor cell (HPC) mobilization. This study assessed the role of CD8+ T cells in HPC cell mobilization and engraftment.STUDY DESIGN AND METHODSMobilization and engraftment were assessed in 192 autologous HPC donors. CD34+, CD4+, and CD8+ T‐cell contents in apheresis products were evaluated. Using a chemotaxis assay, we assessed the effect of purified autologous CD8+ T cells from low and high mobilizers on HPC migration from high to low stromal cell–derived factor (SDF‐1α) concentration gradients. We also assessed CD8+ T‐cell content association with days to neutrophil engraftment.RESULTSThe median number of CD34+ cells/kg was 4.7 × 106. Patients were categorized according to their total CD34+ cell collection quartile distribution into low, moderate, and high mobilizers. We found that HPC products from low mobilizers contained more CD8+ T cells than HPC products from moderate and high mobilizers. Chemotaxis assays showed depletion of CD8+ T cells enhances HPC mobilization independent of SDF‐1α concentration. Neutrophil engraftment analysis showed that the higher the CD8+ T‐cell content per unit CD34+ cell, the faster the rate of engraftment.CONCLUSIONOur findings suggest CD8+ T cells inhibit HPC mobilization and facilitate homing and engraftment.

The contributions of mesenchymal stem cells (MSCs) to tumour growth and stroma formation are poorly understood. Tumour cells can transfer genetic information and modulate cell signalling in other cells through the release of extracellular vesicles (EVs). We examined the contribution of EV‐mediated inter‐cellular signalling between bone marrow MSCs and tumour cells in human cholangiocarcinoma, highly desmoplastic cancers that are characterized by tumour cells closely intertwined within a dense fibrous stroma. Exposure of MSCs to tumour cell–derived EVs enhanced MSC migratory capability and expression of alpha‐smooth muscle actin mRNA, in addition to mRNA expression and release of CXCL‐1, CCL2 and IL‐6. Conditioned media from MSCs exposed to tumour cell–derived EVs increased STAT‐3 phosphorylation and proliferation in tumour cells. These effects were completely blocked by anti‐IL‐6R antibody. In conclusion, tumour cell–derived EVs can contribute to the generation of tumour stroma through fibroblastic differentiation of MSCs, and can also selectively modulate the cellular release of soluble factors such as IL‐6 by MSCs that can, in turn, alter tumour cell proliferation. Thus, malignant cells can “educate” MSCs to induce local microenvironmental changes that enhance tumour cell growth.