Abstract
Efforts to develop peripheral blood-derived nature killer (NK) cells into therapeutic products have been hampered by these cells' low abundance and histoincompatibility. On the other hand, derivation of NK-like cells from more abundant cell sources such as embryonic stem cells (ESCs) and umbilical cord blood (UCB) requires the selection of rare CD34+ cells. Thus, we sought to convert adipose-derived stem cells (ADSCs), which are abundant and natively CD34+, into NK-like cells. When grown in hematopoietic induction medium, ADSCs formed sphere clusters and expressed hematopoietic markers CD34, CD45, and KDR. Further induction in NK cell-specific medium resulted in a population of cells that expressed NK cell marker CD56, and thus termed ADSC-NK. Alternatively, the hematopoietically induced ADSCs were transduced with NK cell-specific transcription factor E4BP4 prior to induction in NK cell-specific medium. This latter population of cells, termed ADSC-NKE, expressed CD56 and additional NK cell markers such as CD16, CD94, CD158, CD314, FasL, and NKp46. ADSC-NKE was as potent as NK leukemia cell NKL in killing breast cancer cell MCF7 and prostate cancer cells DU145, PC3, LnCap, DuPro, C4–2 and CWR22, but exhibited no killing activity toward normal endothelial and smooth muscle cells. In nude mice test ADSC-NKE was able to significantly delay the progression of tumors formed by MCF7 and PC3. When injected into immunocompetent rats, ADSC-NKE was detectable in bone marrow and spleen for at least 5 weeks. Together, these results suggest that ADSCs can be converted into NK-like cells with anti-tumor activities.
Highlights
Natural killer (NK) cells are an important component of the immune system [1]
Hematopoietic differentiation of adipose-derived stem cells (ADSCs) When cultured in hematopoietic induction medium for one week, ADSCs detached from plastic surface to form sphere clusters (Fig. 1A) and expressed CD34, CD45, and KDR at much higher levels than un-induced ADSCs (Fig. 1B&C)
While un-induced ADSC had no detectable level of E4BP4 expression, ADSC-NK and ADSC-NKE expressed incrementally higher levels of E4BP4 (Fig. 2A)
Summary
Natural killer (NK) cells are an important component of the immune system [1] Due to their ability to selectively kill target cells without prior sensitization, there have been intense interests to develop them into anti-cancer and anti-virus agents. Prolonged culture leads to NK cell exhaustion; that is, the resulting cells become ineffective in killing target cells and die within a few days after infusion into the recipient [2]. In recent years there have been attempts to generate NK cells from more abundant cell sources, such as embryonic stem cell (ESC) and umbilical cord blood (UCB) [3,4,5,6,7,8]
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