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New Functional Marker Gets the Most from MSCs

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Review of “Downregulation of Melanoma Cell Adhesion Molecule (MCAM-CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells” from Stem Cells Translational Medicine by Stuart P. Atkinson

To reach the huge numbers often required for the therapeutic application of stem cells to human patients, in vitro expansion is often required. However, long-term culture of cells such as mesenchymal stem cells (MSCs) can lead to cellular senescence which drastically reduces their clinical utility [1, 2]. But what if there existed a means to identify the useful cells from such long-term cultures?

In a new Stem Cells Translational Medicine study, researchers from the laboratory of Hong Bae Jeon (MEDIPOST Co., Ltd., Republic of Korea) searched for senescence-related factors in MSCs derived from human umbilical cord blood. Excitingly, they soon discovered that the loss of the melanoma cell adhesion molecule (MCAM/CD146) cell surface protein led to accelerated senescence. Could they have discovered a means to select only the most useful MSCs and enhance their therapeutic relevance [3]?

As a first step, the authors monitored the expansion of human umbilical cord MSCs in vitro, discovering that MSC growth rates diminished after 5 passages alongside a decrease in stem-cell gene expression and telomerase activity. Additionally, the authors observed an increase in senescence-associated factors and a decrease in osteoblast differentiation capacity within the same cells.

Interestingly, while monitoring changes in cell-surface marker expression, the study found a significant correlation between a reduction in MCAM/CD146 expression and increased MSC passage number (See Figure). When the authors assessed MSCs at an intermediate passage, they discovered that MSCs lacking CD146 expression had a higher potential for developing a senescent phenotype, whereas CD146-expressing cells maintained their stem cell phenotype.

So MCAM/CD146 seems to be an interesting marker, but is it more than this? To assess any functionality, the authors reduced MCAM/CD146 expression via siRNA finding that this accelerated cellular senescence suggesting that MCAM/CD146 may function to maintain the stem cell state. Further experimentation suggested that this function might be to regulate the expression of important cellular senescence regulators such as the Id1- or Twist-family genes [4].

Previous studies from the same laboratory linked the differentiation status of hUCB-MSCs to cell surface markers such as endoglin (CD105) [5] and neural ganglioside (GD2) [6] but this study may represent the first report of a reliable cell surface marker for cellular senescence. The authors hope that their findings will find use in aiding quality-control assessments and enhancing the overall therapeutic potential of hUCB-MSC based therapies.

References

  1. Sethe S, Scutt A, and Stolzing A Aging of mesenchymal stem cells. Ageing Res Rev 2006;5:91-116.
  2. Bustos ML, Huleihel L, Kapetanaki MG, et al. Aging mesenchymal stem cells fail to protect because of impaired migration and antiinflammatory response. Am J Respir Crit Care Med 2014;189:787-798.
  3. Jin HJ, Kwon JH, Kim M, et al. Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells. Stem Cells Translational Medicine 2016;5:427-439.
  4. Isenmann S, Arthur A, Zannettino AC, et al. TWIST family of basic helix-loop-helix transcription factors mediate human mesenchymal stem cell growth and commitment. Stem Cells 2009;27:2457-2468.
  5. Jin HJ, Park SK, Oh W, et al. Down-regulation of CD105 is associated with multi-lineage differentiation in human umbilical cord blood-derived mesenchymal stem cells. Biochem Biophys Res Commun 2009;381:676-681.
  6. Zheng P, Ju L, Jiang B, et al. Chondrogenic differentiation of human umbilical cord bloodderived mesenchymal stem cells by coculture with rabbit chondrocytes. Mol Med Rep 2013;8:1169-1182.