期刊
STEM CELLS
卷 32, 期 9, 页码 2430-2442出版社
WILEY-BLACKWELL
DOI: 10.1002/stem.1729
关键词
Bone marrow stromal cells; Cellular therapy; Clinical translation; Cryopreservation; Immunotherapy; Engraftment; Instant blood-mediated inflammatory reaction
资金
- Swedish Cancer Society [11 0315]
- Children's Cancer Foundation [PROJ11/034]
- Swedish Medical Research Council [K2011-??X-20742-04-6, K2011-65X-12219-15-6]
- VINNOVA [2010-00501]
- Stockholm County Council (ALF) [20110152]
- Cancer Society in Stockholm
- Swedish Society of Medicine
- Tobias Foundation
- Karolinska Institutet
- Swedish Research Council/VINNOVA/Swedish Foundation Strategic Research [6076170]
- Juvenile Diabetes Foundation International
- National Institutes of Health [2U01AI065192-06, GM-62134, AI-068730]
- Medical Research Council
- Osteology Foundation
- Grants-in-Aid for Scientific Research [26702017, 26106709] Funding Source: KAKEN
We have recently reported that therapeutic mesenchymal stromal cells (MSCs) have low engraftment and trigger the instant blood mediated inflammatory reaction (IBMIR) after systemic delivery to patients, resulting in compromised cell function. In order to optimize the product, we compared the immunomodulatory, blood regulatory, and therapeutic properties of freeze-thawed and freshly harvested cells. We found that freeze-thawed MSCs, as opposed to cells harvested from continuous cultures, have impaired immunomodulatory and blood regulatory properties. Freeze-thawed MSCs demonstrated reduced responsiveness to proinflammatory stimuli, an impaired production of anti-inflammatory mediators, increased triggering of the IBMIR, and a strong activation of the complement cascade compared to fresh cells. This resulted in twice the efficiency in lysis of thawed MSCs after 1 hour of serum exposure. We found a 50% and 80% reduction in viable cells with freshly detached as opposed to thawed in vitro cells, indicating a small benefit for fresh cells. In evaluation of clinical response, we report a trend that fresh cells, and cells of low passage, demonstrate improved clinical outcome. Patients treated with freshly harvested cells in low passage had a 100% response rate, twice the response rate of 50% observed in a comparable group of patients treated with freeze-thawed cells at higher passage. We conclude that cryobanked MSCs have reduced immunomodulatory and blood regulatory properties directly after thawing, resulting in faster complement-mediated elimination after blood exposure. These changes seem to be paired by differences in therapeutic efficacy in treatment of immune ailments after hematopoietic stem cell transplantation.
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