Systematic review and meta-analysis of the effect of bone marrow-derived cell therapies on hind limb perfusion.

Preclinical and clinical studies on the administration of bone marrow-derived cells to restore perfusion show conflicting results. We conducted a systematic review and meta-analysis on preclinical studies to assess the efficacy of bone marrow-derived cells in the hind limb ischemia model and identify possible determinants of therapeutic efficacy. In vivo animal studies were identified using a systematic search in PubMed and EMBASE on 10 January 2022. 85 studies were included for systematic review and meta-analysis. Study characteristics and outcome data on relative perfusion were extracted. The pooled mean difference was estimated using a random effects model. Risk of bias was assessed for all included studies. We found a significant increase in perfusion in the affected limb after administration of bone marrow-derived cells compared to that in the control groups. However, there was a high heterogeneity between studies, which could not be explained. There was a high degree of incomplete reporting across studies. We therefore conclude that the current quality of preclinical research is insufficient (low certainty level as per GRADE assessment) to identify specific factors that might improve human clinical trials.

Human Bone Marrow Mononuclear Cells Do Not Improve Limb Perfusion in the Hindlimb Ischemia Model.

Effective treatments for chronic limb-threatening ischemia are lacking. (Pre)clinical studies on administration of bone marrow (BM) mononuclear cells (MNCs) and BM-derived mesenchymal stromal cells (MSCs) have shown variable results and no studies have directly compared administration of human BM MNCs and BM MSCs in in vivo models. We studied the effect of intramuscular administration of human BM-derived MNCs and MSCs on limb perfusion in the murine hindlimb ischemia (HLI) model. Human BM MNCs and MSCs were obtained from healthy consenting donors. Both cell types were cryopreserved before use. Twenty-four hours after induction of HLI, nude NMRI mice were randomized to receive intramuscular administration of human BM MNCs (n = 13), or BM MSCs (n = 14), or vehicle control (n = 19) in various doses. Limb perfusion was measured using laser Doppler imaging on day 0, 1, 4, 7, 10, and 14. Intramuscular injection of human BM MNCs did not improve limb perfusion as compared with vehicle over the 2 weeks after cell administration (P = 0.88, mean relative perfusion for vehicle 0.56 ± 0.04 and 0.53 ± 0.04 for BM MNCs at day 14). Administration of human BM MSCs significantly improved limb perfusion as compared with both BM MNCs and vehicle (P ≤ 0.001, mean relative perfusion at day 14 0.79 ± 0.06). Our data suggest that BM MNCs are less suitable than BM MSCs for cell-based therapy that aims to restore perfusion.

Evaluation of bone marrow-derived cell-based therapies in the hindlimb ischaemia model: a protocol for a systematic review and meta-analysis.

OBJECTIVE: Bone marrow(BM)-derived cell-based therapies for critical limb ischamia showed less clinical benefit than expected. While this might be due to patient-specific factors, it remains possible that important details were lost in the bench-to-clinic translation. The hindlimb ischaemia model is the golden standard to evaluate cell-based therapies aimed at promoting neovascularisation. To inform future trial design and identify potential knowledge gaps, we propose a systematic review and meta-analysis of preclinical evidence to assess the efficacy of BM-derived cell administration in restoring relative perfusion in the hind limb model and identify determinants of therapeutic efficacy. SEARCH STRATEGY: PubMed and EMBASE were searched for prospective studies in which the hindlimb ischaemia model was used to assess BM-derived therapies. SCREENING AND ANNOTATION: Studies with an outcome measure related to relative perfusion of the hindlimb will be included. Study characteristics which include model-related factors as well as details on BM therapy will be extracted. DATA MANAGEMENT AND REPORTING: For the primary analysis, a random effects model will be constructed using the mean difference calculated from the maximum relative perfusion for each study arm in each study. A separate model will be constructed using the relative perfusion at the latest time point in each study. We will also assess the risk of bias using the SYRCLE tool for internal validity. Subgroup analysis will be performed on animal characteristics, administration route, dose and cell characteristics such as the cell donor. PROSPERO REGISTRATION NUMBER: This protocol has been registered at PROSPERO (CRD2021226592).