Abstract
Clinical use of umbilical cord blood has typically been limited by the need to expand hematopoietic stem and progenitor cells (HSPC) ex vivo. This expansion is challenging due to the accumulation of secreted signaling factors in the culture that have a negative regulatory effect on HSPC output. Strategies for global regulation of these factors through dilution have been developed, but do not accommodate the dynamic nature or inherent variability of hematopoietic cell culture. We have developed a mathematical model to simulate the impact of feedback control on in vitro hematopoiesis, and used it to design a proportional-integral-derivative (PID) control algorithm. This algorithm was implemented with a fed-batch bioreactor to regulate the concentrations of secreted factors. Controlling the concentration of a key target factor, TGF-β1, through dilution limited the negative effect it had on HSPCs, and allowed global control of other similarly-produced inhibitory endogenous factors. The PID control algorithm effectively maintained the target soluble factor at the target concentration. We show that feedback controlled dilution is predicted to be a more cost effective dilution strategy compared to other open-loop strategies, and can enhance HSPC expansion in short term culture. This study demonstrates the utility of secreted factor process control strategies to optimize stem cell culture systems, and motivates the development of multi-analyte protein sensors to automate the manufacturing of cell therapies.
Highlights
Hematopoietic stem cell (HSC) transplantation has been used for several decades to successfully treat various pathologies
When used for the ex vivo expansion of hematopoietic stem and progenitor cells (HSPC), further development of this bioprocess may enable the use of Umbilical cord blood (UCB) for transplantation in adult patients
We have developed a new empirical model of hematopoietic cell culture and used it to design a feedback control strategy for regulating concentrations of inhibitory secreted factors
Summary
Hematopoietic stem cell (HSC) transplantation has been used for several decades to successfully treat various pathologies. Umbilical cord blood (UCB) derived HSCs offer several advantages over traditional bone marrow or mobilized peripheral blood derived HSCs, including robust long-term immune reconstitution and reduced incidence of graft-versus-host disease [1, 2]. Lower cell numbers in UCB units have typically limited its use to pediatric patients [3]. A robust bioprocess to expand both HSCs for long-term engraftment and progenitor cells. PID Feedback Control for Blood Stem Cell Culture doctoral fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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