Raphael C. Bosse

Detailed analysis of bone marrow from patients with ischemic heart disease and left ventricular dysfunction BM CD34, CD11b, and clonogenic capacity as biomarkers for clinical outcomes

Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. Methods and Results: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%–2.7% in other cohorts; P<0.05). BM-derived endothelial colonies were significantly decreased (P<0.05). Increased BM CD11b+ cells associated with worse LV ejection fraction (LVEF) after AMI (P<0.05). Increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P=0.03, for patients with AMI and +6.6% versus −0.02%; P=0.021 for patients with chronic IHD). In addition, decreased BM CD34+ percentage in patients with chronic IHD correlated with decrement in LVEF (−2.9% versus +0.7%; P=0.0355). Conclusions: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. Clinical Trial Registrations: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00684021, NCT00684060, and NCT00824005Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. Methods and Results: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%–2.7% in other cohorts; P <0.05). BM-derived endothelial colonies were significantly decreased ( P <0.05). Increased BM CD11b+ cells associated with worse LV ejection fraction (LVEF) after AMI ( P <0.05). Increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P =0.03, for patients with AMI and +6.6% versus −0.02%; P =0.021 for patients with chronic IHD). In addition, decreased BM CD34+ percentage in patients with chronic IHD correlated with decrement in LVEF (−2.9% versus +0.7%; P =0.0355). Conclusions: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. Clinical Trial Registrations: URL: . Unique identifiers: [NCT00684021][1], [NCT00684060][2], and [NCT00824005][3] # Novelty and Significance {#article-title-31} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00684021&atom=%2Fcircresaha%2F115%2F10%2F867.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00684060&atom=%2Fcircresaha%2F115%2F10%2F867.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00824005&atom=%2Fcircresaha%2F115%2F10%2F867.atom

Acute myeloid leukemia in the vascular niche

The greatest challenge in treating acute myeloid leukemia (AML) is refractory disease. With approximately 60-80% of AML patients dying of relapsed disease, there is an urgent need to define and target mechanisms of drug resistance. Unfortunately, targeting cell-intrinsic resistance has failed to improve clinical outcomes in AML. Emerging data show that cell-extrinsic factors in the bone marrow microenvironment protect and support AML cells. The vascular niche, in particular, regulates AML cell survival and cell cycling by both paracrine secretion and adhesive contact with endothelial cells. Moreover, AML cells can functionally integrate within vascular endothelia, undergo quiescence, and resist cytotoxic chemotherapy. Together, these findings support the notion of blood vessels as sanctuary sites for AML. Therefore, vascular targeting agents may serve to remit AML. Several early phase clinical trials have tested anti-angiogenic agents, leukemia mobilizing agents, and vascular disrupting agents in AML patients. In general, these agents can be safely administered to AML patients and cardiovascular side effects were reported. Response rates to vascular targeting agents in AML have been modest; however, a majority of vascular targeting trials in AML are monotherapy in design and indiscriminate in patient recruitment. When considering the chemosensitizing effects of targeting the microenvironment, there is a strong rationale to build upon these early phase clinical trials and initiate phase IB/II trials of combination therapy where vascular targeting agents are positioned as priming agents for cytotoxic chemotherapy.

Chemosensitizing AML cells by targeting bone marrow endothelial cells

Refractory disease is the greatest challenge in treating patients with acute myeloid leukemia (AML). Blood vessels may serve as sanctuary sites for AML. When AML cells were co-cultured with bone marrow endothelial cells (BMECs), a greater proportion of leukemia cells were in G0/G1. This led us to a strategy of targeting BMECs with tubulin-binding combretastatins, causing BMECs to lose their flat phenotype, degrade their cytoskeleton, cease growth, and impair migration despite unchanged BMEC viability and metabolism. Combretastatins also caused downregulation of BMEC adhesion molecules known to tether AML cells, including vascular cell adhesion molecule (VCAM)-1 and vascular endothelial (VE)-cadherin. When AML-BMEC co-cultures were treated with combretastatins, a significantly greater proportion of AML cells dislodged from BMECs and entered the G2/M cell cycle, suggesting enhanced susceptibility to cell cycle agents. Indeed, the combination of combretastatins and cytotoxic chemotherapy enhanced additive AML cell death. In vivo mice xenograft studies confirmed this finding by revealing complete AML regression after treatment with combretastatins and cytotoxic chemotherapy. Beyond highlighting the pathologic role of BMECs in the leukemia microenvironment as a protective reservoir of disease, these results support a new strategy for using vascular-targeting combretastatins in combination with cytotoxic chemotherapy to treat AML.

Detailed Analysis of Bone Marrow From Patients With Ischemic Heart Disease and Left Ventricular Dysfunction

Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. Methods and Results: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%–2.7% in other cohorts; P<0.05). BM-derived endothelial colonies were significantly decreased (P<0.05). Increased BM CD11b+ cells associated with worse LV ejection fraction (LVEF) after AMI (P<0.05). Increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P=0.03, for patients with AMI and +6.6% versus −0.02%; P=0.021 for patients with chronic IHD). In addition, decreased BM CD34+ percentage in patients with chronic IHD correlated with decrement in LVEF (−2.9% versus +0.7%; P=0.0355). Conclusions: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. Clinical Trial Registrations: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00684021, NCT00684060, and NCT00824005Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. Methods and Results: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%–2.7% in other cohorts; P <0.05). BM-derived endothelial colonies were significantly decreased ( P <0.05). Increased BM CD11b+ cells associated with worse LV ejection fraction (LVEF) after AMI ( P <0.05). Increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P =0.03, for patients with AMI and +6.6% versus −0.02%; P =0.021 for patients with chronic IHD). In addition, decreased BM CD34+ percentage in patients with chronic IHD correlated with decrement in LVEF (−2.9% versus +0.7%; P =0.0355). Conclusions: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. Clinical Trial Registrations: URL: . Unique identifiers: [NCT00684021][1], [NCT00684060][2], and [NCT00824005][3] # Novelty and Significance {#article-title-31} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00684021&atom=%2Fcircresaha%2F115%2F10%2F867.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00684060&atom=%2Fcircresaha%2F115%2F10%2F867.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00824005&atom=%2Fcircresaha%2F115%2F10%2F867.atom

Detailed Analysis of Bone Marrow From Patients With Ischemic Heart Disease and Left Ventricular DysfunctionNovelty and Significance

Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. Methods and Results: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%–2.7% in other cohorts; P<0.05). BM-derived endothelial colonies were significantly decreased (P<0.05). Increased BM CD11b+ cells associated with worse LV ejection fraction (LVEF) after AMI (P<0.05). Increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P=0.03, for patients with AMI and +6.6% versus −0.02%; P=0.021 for patients with chronic IHD). In addition, decreased BM CD34+ percentage in patients with chronic IHD correlated with decrement in LVEF (−2.9% versus +0.7%; P=0.0355). Conclusions: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. Clinical Trial Registrations: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00684021, NCT00684060, and NCT00824005Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. Methods and Results: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%–2.7% in other cohorts; P <0.05). BM-derived endothelial colonies were significantly decreased ( P <0.05). Increased BM CD11b+ cells associated with worse LV ejection fraction (LVEF) after AMI ( P <0.05). Increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P =0.03, for patients with AMI and +6.6% versus −0.02%; P =0.021 for patients with chronic IHD). In addition, decreased BM CD34+ percentage in patients with chronic IHD correlated with decrement in LVEF (−2.9% versus +0.7%; P =0.0355). Conclusions: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. Clinical Trial Registrations: URL: . Unique identifiers: [NCT00684021][1], [NCT00684060][2], and [NCT00824005][3] # Novelty and Significance {#article-title-31} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00684021&atom=%2Fcircresaha%2F115%2F10%2F867.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00684060&atom=%2Fcircresaha%2F115%2F10%2F867.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00824005&atom=%2Fcircresaha%2F115%2F10%2F867.atom

Detailed Analysis of Bone Marrow From Patients With Ischemic Heart Disease and Left Ventricular DysfunctionNovelty and Significance: BM CD34, CD11b, and Clonogenic Capacity as Biomarkers for Clinical Outcomes

Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. Methods and Results: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%–2.7% in other cohorts; P<0.05). BM-derived endothelial colonies were significantly decreased (P<0.05). Increased BM CD11b+ cells associated with worse LV ejection fraction (LVEF) after AMI (P<0.05). Increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P=0.03, for patients with AMI and +6.6% versus −0.02%; P=0.021 for patients with chronic IHD). In addition, decreased BM CD34+ percentage in patients with chronic IHD correlated with decrement in LVEF (−2.9% versus +0.7%; P=0.0355). Conclusions: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. Clinical Trial Registrations: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00684021, NCT00684060, and NCT00824005Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. Methods and Results: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%–2.7% in other cohorts; P <0.05). BM-derived endothelial colonies were significantly decreased ( P <0.05). Increased BM CD11b+ cells associated with worse LV ejection fraction (LVEF) after AMI ( P <0.05). Increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P =0.03, for patients with AMI and +6.6% versus −0.02%; P =0.021 for patients with chronic IHD). In addition, decreased BM CD34+ percentage in patients with chronic IHD correlated with decrement in LVEF (−2.9% versus +0.7%; P =0.0355). Conclusions: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. Clinical Trial Registrations: URL: . Unique identifiers: [NCT00684021][1], [NCT00684060][2], and [NCT00824005][3] # Novelty and Significance {#article-title-31} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00684021&atom=%2Fcircresaha%2F115%2F10%2F867.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00684060&atom=%2Fcircresaha%2F115%2F10%2F867.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00824005&atom=%2Fcircresaha%2F115%2F10%2F867.atom