A Preview of Selected Articles.

Current limitations to the systemic administration of mesenchymal stem cells (MSC) as a treatment for a range of indications, including kidney disease and damage 1, include entrapment in the lungs and low levels of target tissue retention. Therefore, the development of novel methods to improve MSC homing and increase engraftment may significantly boost therapeutic outcomes. Currently studied approaches include the overexpression of specific homing factors, alteration of the administration method employed, cell pretreatment/conditioning, and more interestingly, cell surface engineering and the modification of the target tissue 2. Our first Featured Article from Zou et al. describes how cell surface coating with an antibody that targets a kidney damage‐associated protein enhances MSC retention in the ischemic kidney and provides a welcome boost to therapeutic efficacy. In a related article, Burks et al. report that the application of kidney‐targeted pulsed focused ultrasound therapy alongside MSC infusion improves the treatment of acute kidney injury.

While a significant proportion of MSC‐based studies employ cells derived from the adult bone marrow or adipose tissue, there exist alternative MSC sources that may provide better anti‐inflammatory and immunomodulatory control. Human fetal MSCs derived from extraembryonic tissues such as the placenta, umbilical cord, or amniotic fluid display longer telomeres, active telomerase, and a greater expansion capacity 3. Meanwhile, MSCs differentiated from pluripotent stem cells (PSC‐MSCs) such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) may provide the large numbers of early passage MSCs required for optimal therapeutic efficacy and, for iPSCs derived from elderly patients, a “rejuvenated” MSC phenotype 4. Our second Featured Article from Hawkins et al. establishes that ESC‐MSCs hold more potential for the treatment of hypoxia‐ischemia in the brain than fetal MSCs, partly due to stimulated interleukin (IL)‐13 production. In a related article, Li et al. describe how soluble factors secreted from iPSC‐MSCs modulate immune responses following transplantation into a host‐versus‐graft reaction mouse model by inhibiting the cleavage of caspases.

Featured Articles

Antibody‐Targeting Improves MSC Therapy in the Injured Kidney

The upregulation and sustained expression of the kidney injury molecule (KIM)‐1 transmembrane protein in response to kidney injury permitted researchers from the laboratory of Xiangyang Zhu and Lilach O. Lerman (Mayo Clinic, Rochester, Minnesota, USA) to develop a novel strategy to enhance the therapeutic value of MSC infusions. In their new study, Zou et al. demonstrated that coating allogenic adipose‐derived MSCs with antibodies directed against KIM‐1 had little effect on viability or proliferation; however, the KIM‐1‐targetted MSCs displayed increased homing and retention following systemic administration in a mouse model of ischemic kidney injury 5. Overall, the benefits brought by surface coating MSCs with antibodies translated to improved renal perfusion and capillary density, as well as attenuated oxidative damage, apoptosis, and fibrosis. The authors hope that their approach will contribute to the creation of novel strategies for effective kidney injury repair.

DOI: 10.1002/sctm.17-0186

PSC‐Derived MSC: An Optimal Source for Neuroprotective Therapies?

The anti‐inflammatory and immunomodulatory characteristics of MSCs have led to their extensive therapeutic application in a wide range of disease and disorders. We can derive MSCs from a number of different sources; however, we still need to identify the optimal source for specific applications. A new study from the laboratories of Kate E. Hawkins and Pascale V. Guillot (University College London, UK) compared the neuroprotective capacity of PSC‐MSCs and fetal MSCs derived from amniotic fluid. Hawkins et al. discovered that ESC‐MSCs displayed superior neuroprotective potential in the hypoxic‐ischemic mouse brain, a feat linked to the enhanced production of anti‐inflammatory factors such as IL‐13 6. Furthermore, the authors described neuroprotective similarities between ESC‐MSCs and iPSC‐MSCs, suggesting that iPSC‐derived cells may also find use in neuroprotective therapies. While fetal MSCs present certain advantages over adult MSCs, this new study indicates that PSC‐MSCs represent the optimal cell source for application in neuroprotective strategies.

DOI: 10.1002/sctm.17-0260

Related Articles

Pulsed Focused Ultrasound and MSC Infusions: A Potent New Strategy for Kidney Repair?

While our Featured Article from Zou et al. sought to surface modify MSCs to enhance homing to the injured kidney, a related study published in from the laboratory of Scott R. Burks (NIH, Bethesda, Maryland, USA) instead modulated the kidney by applying noninvasive image‐guided pulsed focused ultrasound to improve the therapeutic outcome of MSC infusions 7. Burks et al. demonstrated how ultrasound directed at the injured mouse kidney elicited transient increases in vascular integrins and chemoattractants and promoted induced homing permeability and retention (EHPR) of infused MSCs. This potent new strategy permitted MSCs to generate a more anti‐inflammatory environment in the injured kidney, leading to increased recovery of renal function compared to MSC infusion alone. The authors suggest that their new approach could represent a simple and noninvasive means to significantly improve MSC therapies aimed at preventing and/or treating acute kidney injury in human patients.

DOI: 10.1002/stem.1965

Investigating Immunomodulation By Induced PSC‐Derived MSC

MSCs differentiated from iPSCs may represent a patient‐specific and renewable source of cells for therapeutic applications, but their ability to modulate immune responses in vivo remained unknown until the publication of a study from the laboratories of Qing‐Ling Fu (Sun Yat‐sen University, Guangzhou, China) and Zhongquan Qi (Xiamen University, Fujian, China) 8. Li et al. investigated T cell responses in an iPSC‐MSC‐transplanted host‐versus‐graft reaction mouse model finding that iPSC‐MSCs survived well and exhibited enhanced immunosuppressive activities. Interestingly, the authors linked these enhancements, which included the suppression of T cell responses, decreased T helper cell frequencies, and increased regulatory T cells number, to the inhibition of caspase cleavage by iPSC‐MSC secreted factors. While this study underlines the great potential for iPSC‐MSCs in immunomodulation, it also provides proof of a novel mechanism underlying iPSC‐MSC‐based immunomodulatory effects.

DOI: 10.1002/stem.2638