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Growth Factor Content in Human Sera Affects the Isolation of Mesangiogenic Progenitor Cells (MPCs) from Human Bone
Marina Montali1, Serena Barachini1, Francesca M Panvini1
1Department of Clinical and Experimental Medicine, University of Pisa Pisa, Italy.
Abstract:
Mesangiogenic Progenitor Cells (MPCs) are human bone marrow-derived multipotent cells, isolated in vitro under selective culture conditions and shown to retain both mesengenic and angiogenic potential. MPCs also co-isolated with multipotent stromal cells (MSCs) when bone marrow primary cultures were set up for clinical applications, using human serum (HS) in place of fetal bovine serum (FBS). MPC culture purity (over 95%) is strictly dependent on HS supplementation with significant batch-to-batch variability. In the present paper we screened different sources of commercially available pooled human AB type serum (PhABS) for their ability to promote MPC production under selective culture conditions. As the majority of "contaminating" cells in MPC cultures were represented by MSC-like cells, we hypothesized a role by differentiating agents present in the sera. Therefore, we tested a number of growth factors (hGF) and found that higher concentrations of FGF-2, EGF, PDGF-AB, and VEGF-A as well as lower concentration of IGF-1 give sub-optimal MPC recovery. Gene expression analysis of hGF receptors was also carried out both in MSCs and MPCs, suggesting that FGF-2, EGF, and PDGF-AB could act promoting MSC proliferation, while VEGF-A contribute to MSC-like cell contamination, triggering MPC differentiation. Here we demonstrated that managing hGF contents, together with applying specific receptors inhibitors (Erlotinib-HCl and Nintedanib), could significantly mitigate the batch-to-batch variability related to serum supplementation. These data represent a fundamental milestone in view of manufacturing MPC-based medicinal products.
Insights
Human bone marrow-derived Mesangiogenic Progenitor Cells (MPCs) production for clinical use is variable. Managing growth factors and using inhibitors mitigates this variability, paving the way for manufacturing MPC-based products.
Area of Science:
- Stem Cell Biology
- Regenerative Medicine
- Cell Therapy Manufacturing
Background:
- Mesangiogenic Progenitor Cells (MPCs) are multipotent human bone marrow cells with mesengenic and angiogenic potential.
- MPC isolation for clinical applications co-isolates multipotent stromal cells (MSCs), with purity dependent on human serum (HS) variability.
- Existing methods show significant batch-to-batch variability in HS, impacting MPC production consistency.
Purpose of the Study:
- To screen pooled human AB serum (PhABS) sources for optimal MPC production.
- To investigate the role of human growth factors (hGF) in MPC culture purity and MSC contamination.
- To develop strategies for mitigating serum-related variability in MPC manufacturing.
Main Methods:
- Screening of commercially available pooled human AB serum (PhABS) for MPC production.
- Testing the effects of various human growth factors (hGF) on MPC recovery and MSC contamination.
- Gene expression analysis of hGF receptors in MSCs and MPCs.
- Application of specific receptor inhibitors (Erlotinib-HCl, Nintedanib) to manage variability.
Main Results:
- Higher concentrations of FGF-2, EGF, PDGF-AB, and lower IGF-1 resulted in sub-optimal MPC recovery.
- VEGF-A was implicated in triggering MPC differentiation and MSC-like cell contamination.
- FGF-2, EGF, and PDGF-AB may promote MSC proliferation, while VEGF-A contributes to contamination.
- Managing hGF levels and using receptor inhibitors significantly reduced batch-to-batch variability.
Conclusions:
- Human growth factor composition in serum significantly impacts MPC production and purity.
- Specific hGFs and their receptors play distinct roles in MPC maintenance versus MSC contamination.
- Strategies involving hGF management and receptor inhibition are crucial for reproducible MPC manufacturing.
- This study provides a fundamental step towards the clinical manufacturing of MPC-based medicinal products.
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