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CAMKK1 Overexpression: A New and Effective Strategy to Improve Cardiac Repair?



Review of “A Novel Role for CAMKK1 in the Regulation of the Mesenchymal Stem Cell Secretome” from STEM CELLS Translational Medicine by Stuart P. Atkinson

We are now beginning to recognize that paracrine effects represent the primary driving therapeutic force behind mesenchymal stem cell (MSC)-based treatments. Therefore, the focus of many research teams has shifted towards deciphering the essential MSC-derived proteins involved and boosting the expression of said proteins to potentiate any pro-regenerative effects.

Researchers from the laboratory of Maritza E. Mayorga (Northeast Ohio Medical University, USA) previously determined that pre-treatment with TGFβ1 potentiated the ability of MSCs to treat acute myocardial infarction (AMI) via the downregulation of Dab2 tumor suppressor expression [1]. Now, Dong et al. have investigated the consequences of Dab2 downregulation in a new STEM CELLS Translational Medicine study, demonstrating a novel role for calcium/calmodulin-dependent protein kinase kinase-1 (CAMKK1) in the modulation of MSC secreted factors and a potential exciting means to enhance MSC-based cardiac repair [2].

Dong et al. assessed protein expression changes following the downregulation of Dab2 expression in MSCs by three means (Dab-2 siRNA, miR-145 expression, and TGFβ1 pre-treatment) and concentrated on CAMKK1 given its overexpression under all three conditions and its novelty to the field of regenerative medicine. Previous studies have indicated that CAMKK1 activates CAMK1 and CAMKIV and modulate several important pathways, including mTORC and AMPK signaling [3-5]. 

To assess whether CAMKK1 can improve cardiac tissue repair, the group overexpressed CAMKK1 in MSCs and injected the modified MSCs or their conditioned medium (CM) into infarcted cardiac tissue at the time of AMI. Encouragingly, CAMKKI overexpression induced significant improvements in cardiac function when compared to unmodified MSCs (and their CM) including a decrease in myocardial scar formation and an increase in vascular density. Importantly, the pro-regenerative effects of CM from modified MSCs suggest that CAMKK1 acts by modulating the secretome of MSCs to produce elevated levels of pro-reparative factors. Finally, the authors also discovered similar elevated cardiac repair following the transient overexpression of CAMKK1 in infarcted cardiac tissue via the injection of a CAMKK1 expression plasmid. 

What a study - improved MSC-based cardiac repair and perhaps the beginnings of an effective cell-free strategy! However, the authors hope to go further and identify CAMKK1 downstream effects to understand the relevant pathways and their contributions to cardiac repair.  

Keep tuned to the Stem Cells Portal to hear all the news on this compelling new strategy for cardiac repair!

Discussion Points

  • Does CAMKK1 overexpression represent a viable means to boost cardiac repair?
  • What pro-reparative MSC secreted factors are important to cardiac repair?
  • What are the important CAMKK1 downstream signaling pathways involved?


  1. Mayorga ME, Dong F, Sundararaman S, et al. Central role for disabled-2 in mesenchymal stem cardiac protein expression and functional consequences after engraftment in acute myocardial infarction. Stem Cells Dev 2011;20:681-693.
  2. Dong F, Patnaik S, Duan ZH, et al. A Novel Role for CAMKK1 in the Regulation of the Mesenchymal Stem Cell Secretome. Stem Cells Transl Med 2017;6:1759-1766.
  3. Ferey JL, Brault JJ, Smith CA, et al. Constitutive activation of CaMKKalpha signaling is sufficient but not necessary for mTORC1 activation and growth in mouse skeletal muscle. Am J Physiol Endocrinol Metab 2014;307:E686-694.
  4. Mizuno K, Ris L, Sanchez-Capelo A, et al. Ca2+/calmodulin kinase kinase alpha is dispensable for brain development but is required for distinct memories in male, though not in female, mice. Mol Cell Biol 2006;26:9094-9104.
  5. Witczak CA, Fujii N, Hirshman MF, et al. Ca2+/calmodulin-dependent protein kinase kinase-alpha regulates skeletal muscle glucose uptake independent of AMP-activated protein kinase and Akt activation. Diabetes 2007;56:1403-1409.