Researchers Discover Drug that Improves Fitness of Cells Used in Transplants

Researchers Discover Drug that Improves Fitness of Cells Used in Transplants

A new study by researchers at Children’s Hospital of Philadelphia (CHOP) has revealed that a small molecule drug can enhance the fitness of hematopoietic stem and progenitor cells (HSPCs) used in cell transplants. The study, published in the journal Blood, found that targeting components in the cells called extracellular vesicles (EVs) can relieve stress on the cells when they are modified outside the body, leading to improved performance after transplantation.

The researchers initially set out to understand the role of EVs and assumed that blocking their function would have negative effects on the cells. However, they discovered that blocking EV formation actually improved the cells’ fitness, initiating a stress response that protected them from the challenges of being outside of the body. This finding has potential implications for procedures such as ex vivo gene therapy, where HSPCs are modified outside the body before being transplanted back in.

Hematopoietic stem cell transplantation (HSCT) involves transferring HSPCs from a donor to patients with various diseases. In ex vivo gene therapy, the patient’s own HSPCs are removed, modified, and then transplanted back in. However, maintaining the fitness of these cells outside of the body has been a challenge, as any loss of fitness can hinder the cells’ ability to restore the blood and immune cell system in patients.

The researchers discovered that the secretion of EVs contributes to cell equilibrium and plays a role in maintaining cell function. To explore this role, they exposed mouse and human HSPCs to a small molecule drug called GW4869, which blocks the production of EVs. They found that this exposure led to sustained improvements in cell fitness and transplantation efficiency. Blocking EV production also leveled disparities in cell performance after transplantation into mice.

The study revealed that blocking EV production activates an integrated stress response, protecting the cells from external stressors. The small molecule drug disrupts sphingolipid metabolism, impairing the release of EVs.

This study has important implications for improving the safety and efficiency of HSPC transplantation and ex vivo gene therapy. The drug used in this study shows promise in enhancing the culture and transplantation of HSPCs, potentially expanding patient eligibility for these therapies.


– Stephanie N Hurwitz et al, Neutral sphingomyelinase blockade enhances hematopoietic stem cell fitness through an integrated stress response, Blood (2023). DOI: 10.1182/blood.2023022147
– “Researchers improve fitness of cells used in cell transplants” – Children’s Hospital of Philadelphia (source article)

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