Abstract
Mesenchymal stem cells (MSCs) are recognized as potential treatments for multiple degenerative and inflammatory disorders as a number of animal and human studies have indicated their therapeutic effects. There are also several clinically approved medicinal products that are manufactured using these cells. For such large-scale manufacturing requirements, the in vitro expansion of harvested MSCs is essential. Multiple subculturing of MSCs, however, provokes cellular senescence processes which is known to deteriorate the therapeutic efficacy of the cells. Strategies to rejuvenate or selectively remove senescent MSCs are therefore highly desirable for fostering future clinical applications of these cells. In this present study, we investigated gene expression changes related to cellular senescence of MSCs derived from umbilical cord blood and found that CD26, also known as DPP4, is significantly upregulated upon cellular aging. We further observed that the inhibition of CD26 by genetic or pharmacologic means delayed the cellular aging of MSCs with their multiple passaging in culture. Moreover, the sorting and exclusion of CD26-positive MSCs from heterogenous cell population enhanced in vitro cell attachment and reduced senescence-associated cytokine secretion. CD26-negative MSCs also showed superior therapeutic efficacy in mouse lung emphysema model. Our present results collectively suggest CD26 is a potential novel target for the rejuvenation of senescent MSCs for their use in manufacturing MSC-based applications.
Highlights
Since mesenchymal stem cells (MSCs) were identified as colony-forming cells in addition to hematopoietic stem cells in the bone marrow (Friedenstein et al, 1968), they have attracted the interest of many researchers due to their ability to differentiate into multiple lineages with undemanding culture condition
The differentiation potential of the Human umbilical cord blood (hUCB)-Mesenchymal stem cells (MSCs) was assessed by Von Kossa or oil red O staining after they had been induced to differentiate into osteocytes or adipocytes
A significant decrease was found in the ratio of stained cells at late passages, suggesting a reduced stemness in senescent cells (Supplementary Figure S2D). These results indicated that well-known phenotypes related to senescence were reproduced in hUCB-MSCs
Summary
Since mesenchymal stem cells (MSCs) were identified as colony-forming cells in addition to hematopoietic stem cells in the bone marrow (Friedenstein et al, 1968), they have attracted the interest of many researchers due to their ability to differentiate into multiple lineages with undemanding culture condition. The multipotential differentiation capacity of MSCs led its potential clinical application to tissue repair and regeneration. Once it was suggested MSCs could be used to relieve adverse immune reaction like graft versus host disease (GVHD) after a CD26 Provokes Cellular Senescence bone marrow transplantation (Lazarus et al, 2005; Le Blanc et al, 2008), their role as paracrine effector and immunomodulator emerged. Subsequent studies have revealed that MSCs regulate immune response by secreting anti-inflammatory cytokines such as prostaglandin E2 and transforming growth factor β (Aggarwal and Pittenger, 2005; English et al, 2009). The first drug to be produced using cryopreserved allogeneic adult bone marrow MSCs, Prochymal, was approved by several countries for the treatment of refractory acute GVHD in 2012, and there have been over 1,000 clinical trials that are registered at Clinicaltrials. gov to treat conditions ranging from knee osteoarthritis to Crohn’s disease
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