TY - JOUR
AU - Atkinson, Stuart P.
AB - Sepsis, the leading cause of death in intensive care units, can occur when an infection prompts a systemic hyper-inflammatory response involving the innate immune system.1 The accumulation of neutrophils and macrophages and the overproduction of inflammatory cytokines associated with sepsis can cause severe damage to host tissues and organs and prompt multiorgan failure and death.2,, 3 As with many conditions that involve the immune system, mesenchymal stem cells (MSCs) have been proposed as a potential treatment option; in this case, treatment with MSCs aims to dampen the proinflammatory response to inhibit potential tissue/organ damage. However, we still lack a full understanding of how MSCs convey their immunomodulatory function: do paracrine-acting secreted factors mediate this response, thereby creating the possibility of a cell-free therapeutic approach for sepsis, or does any immunomodulation require the presence of MSCs themselves? One of the major consequences of sepsis is the onset of acute kidney injury, with impaired renal function, renal inflammation, microvascular dysfunction, and endothelial cell injury occurring through several different mechanisms. Can MSC therapy also inhibit serious sepsis-associated conditions such as these? In the first of our Featured Articles this month published in STEM CELLS, Weiss et al. employ mouse models of allogeneic heart transplantation and sepsis to highlight the importance of tailoring MSC-based treatments to the disease as opposed to utilizing MSCs as a one-size-fits-all therapeutic solution.4 In a Related Article published in STEM CELLS Translational Medicine, Cóndor et al. demonstrated that human Wharton's jelly-derived MSCs adequately protected against renal, hepatic, and endothelial dysfunction in a rat model of sepsis.5 The loss of dopaminergic neurons in the substantia nigra and the subsequent loss of dopamine in the striatum leads to the impaired control of movement observed in patients with Parkinson's disease. Replacement of dopamine can alleviate symptoms; however, we currently lack both effective curative strategies for this debilitating disease and model systems that faithfully recapitulate disease characteristics. The guided differentiation of human pluripotent stem cells (hPSCs) may allow for the development of Parkinson's disease models to screen drugs and evaluate potential therapeutics and for the generation of the dopaminergic neurons required for cell replacement therapies. Unfortunately, attempts to model Parkinson's disease employing hPSCs cultured under conventional two-dimensional conditions have not met with great success6-8; however, recent advances in three-dimensional organoid technology may provide a better approach. Of additional importance, questions remain as to the optimal cell type for cell replacement therapies in Parkinson's disease: are we better to transplant mature dopaminergic neurons, or may stem/progenitor cells or immature neurons afford the optimal recovery of function? In the second of our Featured Articles this month published in STEM CELLS, Kwak et al. describe a novel method for the generation of homogenous hPSC-derived midbrain-like organoids that may prove useful for the in vitro modeling of Parkinson's disease.9 In a Related Article published in STEM CELLS Translational Medicine, Qiu et al. reported that transplantation of immature midbrain dopaminergic neurons derived from hPSCs prompted enhanced functional recovery in a Parkinson's disease mouse model when compared with mature neurons and progenitor cells.10 FEATURED ARTICLES Sepsis and Allogeneic Transplantation Models Help to Explore MSC-Induced Immunomodulation In the hope of defining how MSCs convey their immunomodulatory effect, researchers from the laboratory of Andreas R. R. Weiss (Trinity College Dublin, Ireland) compared the administration of MSCs and heat-inactivated MSCs (HI-MSCs), which lose their metabolic and secretory activity but maintain their cellular integrity,11 in two animal models that provoke diverse immunological reactions. The team's recent STEM CELLS article4 employed allogeneic heart transplantation, a T lymphocyte-mediated immune response that prompts graft rejection, and cecal ligation and puncture-induced sepsis, a hyper-inflammatory response involving Open in new tabDownload slide Open in new tabDownload slide neutrophils/macrophages and inflammatory cytokine overproduction that induces severe host tissue/organ damage.3 Analysis of the allogeneic heart transplantation model revealed that control MSCs dose-dependently inhibited T-cell proliferation and significantly improved graft survival; however, HI-MSCs failed to produce any therapeutic effect, suggesting the importance of MSC secreted factors to the inhibition of T-cell mediated allograft rejection. In the case of the sepsis model, the administration of HI-MSCs significantly improved survival, while control MSCs failed to induce any therapeutic effect. The authors provided evidence that increased phagocytosis of HI-MSCs by monocytes compared with control MSCS may explain the immunoprotective effect of HI-MSC in this case. Overall, Weiss et al. establish that MSCs exhibit diverse immunomodulatory mechanisms during disease resolution, suggesting a need to tailor MSC-based therapies to disease types, rather than employing MSC therapy as a one-size-fits-all solution. https://doi.org/10.1002/stem.3165 Parkinson's Disease Modeling with Pluripotent Stem Cell-Derived Midbrain-Like Organoids Recent studies have reported the generation of hPSC-derived midbrain-like organoids (or MOs) that express typical midbrain markers and display structures similar to those observed in the human brain, thereby suggesting their use in disease modeling and drug screening for midbrain-specific neurodegenerative diseases such as Parkinson's disease. However, low-efficiency generation, the immature/heterogeneous structures produced, and their physiologically irrelevant cellular composition have hindered further progress. In a recent STEM CELLS article,9 researchers led by Dong Wook Han (Wuyi University, Jiangmen, China) describe their new protocol for the robust generation of in vivo-like midbrain-like organoids with a homogeneous distribution of midbrain dopaminergic (or mDA) neurons. Kwak et al. report that exposure of hPSCs to a dual SMAD inhibitor combination prompted the efficient and homogenous specification of hPSCs into midbrain-like three-dimensional structures that displayed a global enrichment of dopaminergic neurons. The additional application of a WNT gradient induced regional identity and permitted the development of functionally and electrophysiologically mature midbrain-like organoids that possessed a neuronal organization similar to the in vivo scenario, including the inclusion of functional glial cells such as astrocytes and oligodendrocytes. Finally, and with this last point in mind, the authors highlighted the therapeutic potential of these midbrain-like organoids by demonstrating how treatment with an astrocyte-mediated neurotoxin (MPTP,12,, 13) led to dopaminergic neuron-specific cell death, therefore making these midbrain-like organoids suitable for the in vitro disease modeling of Parkinson's disease. Open in new tabDownload slide Open in new tabDownload slide https://doi.org/10.1002/stem.3163 RELATED ARTICLES Wharton's Jelly-Derived Mesenchymal Stem Cells Attenuate Sepsis-Induced Cellular Dysfunction MSCs derived from the Wharton's jelly, a gelatinous substance within the umbilical cord, exhibit comparable or better immunomodulatory characteristics when compared to MSCs derived from other tissues; therefore, these cells may possess huge promise as a therapeutic option for sepsis-related conditions such as acute kidney injury.14,, 15 To this end, researchers from the laboratory of Lúcia Andrade (University of São Paulo School of Medicine, Brazil) aimed to evaluate the treatment with Wharton's jelly MSCs in a cecal ligation and puncture (or CLP) model of sepsis in rats as a means to protect renal, hepatic, and endothelial cell function. Reporting in a recent STEM CELLS Translational Medicine article,5 Cóndor et al. discovered reduced renal function, measured by lower glomerular filtration rate, by six hours after the induction of sepsis; however, the administration of Wharton's jelly MSCs led to multiple significant alterations, including improved glomerular filtration rate and tubular function, reduced macrophage/monocyte infiltration into the renal tubulointerstitium, and decreased levels of proinflammatory signaling. Furthermore, the study also noted the attenuation of renal cell death, improvements in hepatic function, and an overall increase in survival. Overall, the authors established that Wharton's jelly MSCs protected against the renal, hepatic, and endothelial dysfunction associated with the onset of sepsis in rats and raised hopes that this therapeutic strategy may contribute toward a reduction in sepsis-related mortality rates in human patients. Open in new tabDownload slide Open in new tabDownload slide https://doi.org/10.5966/sctm.2015-0138 Immature Midbrain Dopaminergic Neurons: The Ideal Choice for Parkinson's Disease Treatment? The replacement of lost dopaminergic neurons with hPSC-derived cells represents a promising treatment for Parkinson's disease, and recent studies reported that the “floor-plate” method of dopaminergic neuron differentiation allowed for improved grafting and functional improvements in animal models without any sign of tumorigenesis.16,, 17 However, we lacked a systematic evaluation of whether dopaminergic progenitors or more mature neurons generated via this protocol produced the best long-term survival and functional restoration. In their recent STEM CELLS Translational Medicine article,10 researchers led by Eng King Tan (National Neuroscience Institute), Steve Oh (A-Star), and Li Zeng (National Neuroscience Institute, Singapore) employed the floor-plate method to generate cells representative of different stages of dopaminergic differentiation and assessed engraftment, survival, differentiation, maturation, and functional recovery in a mouse model of Parkinson's disease. Qiu et al. discovered that dopaminergic progenitors, immature neurons, and mature neurons all engrafted into host brains with high viability rates with no sign of neural overgrowth, necrosis, or apoptosis. Interestingly, progenitor cells displayed a limited ability to mature and differentiate in vivo and failed to promote behavioral recovery post-transplantation; however, both immature and mature neurons could promote behavioral recovery, with immature neurons displaying the better results. Overall, the authors provide further evidence for the utility of the floor-plate method and hope that their findings will help to standardize the differentiation stage of transplantable cells employed in therapeutic approaches to Parkinson's disease treatment in human patients. Open in new tabDownload slide Open in new tabDownload slide https://doi.org/10.1002/sctm.16-0470 REFERENCES 1 Dellinger RP , Levy MM, Rhodes A, et al. Surviving sepsis campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012 . Intensive Care Med . 2013 ; 39 : 165 - 228 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Hotchkiss RS , Karl IE. The pathophysiology and treatment of sepsis . N Engl J Med . 2003 ; 348 : 138 - 150 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Chang CL , Leu S, Sung HC, et al. Impact of apoptotic adipose-derived mesenchymal stem cells on attenuating organ damage and reducing mortality in Rat sepsis syndrome induced by cecal puncture and ligation . J Transl Med . 2012 ; 10 : 244 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Weiss ARR , Lee O, Eggenhofer E, et al. Differential effects of heat-inactivated, secretome-deficient MSC and metabolically active MSC in sepsis and allogenic heart transplantation . Stem Cells . 2020 ; 38 : 797 - 807 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Cóndor JM , Rodrigues CE, de Sousa MR, et al. Treatment with human Wharton's jelly-derived mesenchymal stem cells attenuates sepsis-induced kidney injury, liver injury, and endothelial dysfunction . Stem Cells Translational Medicine . 2016 ; 5 : 1048 - 1057 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Soldner F , Hockemeyer D, Beard C, et al. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors . 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Stem Cells Translational Medicine . 2017 ; 6 : 1803 - 1814 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Luk F , de Witte SF, Korevaar SS, et al. Inactivated mesenchymal stem cells maintain immunomodulatory capacity . Stem Cells Dev . 2016 ; 25 : 1342 - 1354 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Meredith GE , Rademacher DJ. MPTP mouse models of Parkinson's disease: an update . J Parkinsons Dis . 2011 ; 1 : 19 - 33 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Smeyne RJ , Jackson-Lewis V. The MPTP model of Parkinson's disease . Brain Res Mol Brain Res . 2005 ; 134 : 57 - 66 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Romanov YA , Svintsitskaya VA, Smirnov VN. Searching for alternative sources of postnatal human mesenchymal stem cells: candidate MSC-like cells from umbilical cord . Stem Cells . 2003 ; 21 : 105 - 110 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Watson N , Divers R, Kedar R, et al. Discarded Wharton jelly of the human umbilical cord: a viable source for mesenchymal stromal cells . Cytotherapy . 2015 ; 17 : 18 - 24 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Kriks S , Shim J-W, Piao J, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease . Nature . 2011 ; 480 : 547 - 551 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Grealish S , Diguet E, Kirkeby A, et al. Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease . Cell Stem Cell . 2014 ; 15 : 653 - 665 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Previews highlight research articles published in the current issue of Stem Cells, putting the results in context for readers. ©AlphaMed Press 2020 This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - A Preview of Selected Articles
JF - Stem Cells
DO - 10.1002/stem.3195
DA - 2020-06-01
UR - https://www.deepdyve.com/lp/oxford-university-press/a-preview-of-selected-articles-iA6yd0qsIq
SP - 713
EP - 715
VL - 38
IS - 6
DP - DeepDyve
ER -