bims-heshmo 2021-12-12 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–12–12
twelve papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Plasma components to protect the endothelial barrier after shock: A role for sphingosine 1-phosphate.
Mesenchymal Stem Cell Extracellular Vesicles Mitigate Vascular Permeability and Injury in the Small Intestine and Lung in a Mouse Model of Hemorrhagic Shock and Trauma.
A Multifunctional, Low-Volume Resuscitation Cocktail Improves Vital Organ Blood Flow and Hemostasis in a Pig Model of Polytrauma with Traumatic Brain Injury.
Reduced cleavage of von willebrand factor by ADAMTS13 is associated with microangiopathic acute kidney injury following trauma.
Autoresuscitation of Poloxamer 188 in Pigs with Traumatic Severe Hemorrhage.
Inhibition of The Interaction Of TREM-1 and eCIRP Attenuates Inflammation and Improves Survival In Hepatic Ischemia/Reperfusion.
Dexmedetomidine Alleviates Gut-Vascular Barrier Damage and Distant Hepatic Injury Following Intestinal Ischemia/Reperfusion Injury in Mice.
Personalized modulation of coagulation factors using a thrombin dynamics model to treat trauma-induced coagulopathy.
Tyrosine kinase nonreceptor 1 (TNK1) knockdown ameliorates hemorrhage shock-induced kidney injury via inhibiting macrophage M1 polarization.
Hemodynamic Effects of Cardiovascular Medications in a Normovolemic and Hemorrhaged Yorkshire-cross Swine Model.
Combined Quantitative (Phospho)proteomics and Mass Spectrometry Imaging Reveal Temporal and Spatial Protein Changes in Human Intestinal Ischemia-Reperfusion.
Non-canonical Wnt signaling promotes directed migration of intestinal stem cells to sites of injury.

Surgery. 2021 Dec 02. pii: S0039-6060(21)01009-6. [Epub ahead of print]

Plasma components to protect the endothelial barrier after shock: A role for sphingosine 1-phosphate.

Lawrence N Diebel, David M Liberati, Timothy Hla, Steven Swendeman.

BACKGROUND: Hemorrhagic shock leads to endothelial glycocalyx shedding, endothelial cellular inflammation, and increased vascular permeability. Early plasma administration improves survival in severely injured patients; this may be due in part to its ability to ameliorate this trauma-induced endotheliopathy. The protective effect of early plasma administration may be due to its sphingosine 1-phosphate content. Principle carriers of plasma sphingosine 1-phosphate include apolipoprotein M and albumin. The relative roles of these carriers on sphingosine 1-phosphate protective effects are unknown and were studied in an in vitro model of microcirculation.
METHODS: Endothelial cell monolayers were established in microfluidic perfusion devices and exposed to control or biomimetic shock conditions. Sphingosine 1-phosphate, albumin + sphingosine 1-phosphate, or apolipoprotein M + sphingosine 1-phosphate were added later to the perfusate. Biomarkers of endothelial and glycocalyx activation and damage were then determined.
RESULTS: Sphingosine 1-phosphate preserved endothelial and glycocalyx barrier function after exposure to conditions of shock in the microcirculation. The protective effect was related to sphingosine 1-phosphate chaperones; the apolipoprotein M loaded with sphingosine 1-phosphate had the most profound effect.
CONCLUSION: Carrier-based sphingosine 1-phosphate may be a useful adjunct in early hemorrhagic shock resuscitation.

DOI: https://doi.org/10.1016/j.surg.2021.08.068
J Trauma Acute Care Surg. 2021 Dec 06.

Mesenchymal Stem Cell Extracellular Vesicles Mitigate Vascular Permeability and Injury in the Small Intestine and Lung in a Mouse Model of Hemorrhagic Shock and Trauma.

Mark Barry, Alpa Trivedi, Praneeti Pathipati, Byron Y Miyazawa, Lindsay R Vivona, Padma Priya Togarrati, Manisha Khakoo, Heather Tanner, Philip Norris, Shibani Pati.

BACKGROUND: Hemorrhagic shock and trauma (HS/T)-induced gut injury may play a critical role in the development of multi-organ failure. Novel therapies that target gut injury and vascular permeability early after HS/T could have substantial impacts on trauma patients. In this study we investigate the therapeutic potential of human mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC EVs) in vivo in HS/T in mice and in vitro in Caco-2 human intestinal epithelial cells.
METHODS: In vivo, using a mouse model of HS/T, vascular permeability to a 10kD dextran dye and histopathologic injury in the small intestine and lungs were measured among mice. Groups were 1) sham, 2) HS/T + lactated Ringer's (LR), 3) HS/T + MSCs, and 4) HS/T + MSC EVs. In vitro, Caco-2 cell monolayer integrity was evaluated by an epithelial cell impedance assay. Caco-2 cells were pre-treated with control media, MSC conditioned media (CM), or MSC EVs, then challenged with hydrogen peroxide (H2O2).
RESULTS: In vivo, both MSCs and MSC EVs significantly reduced vascular permeability in the small intestine (fluorescence units: Sham 456 ± 88, LR 1067 ± 295, MSC 765 ± 258, MSC EV 715 ± 200) and lung (Sham 297 ± 155, LR 791 ± 331, MSC 331 ± 172, MSC EV 303 ± 88). Histopathologic injury in the small intestine and lung was also attenuated by MSCs and MSC EVs. In vitro, MSC CM but not MSC EVs attenuated the increased permeability among Caco-2 cell monolayers challenged with H2O2.
CONCLUSION: MSC EVs recapitulate the effects of MSCs in reducing vascular permeability and injury in the small intestine and lungs in vivo, suggesting MSC EVs may be a potential cell-free therapy targeting multi-organ dysfunction in HS/T. This is the first study to demonstrate MSC EVs improve both gut and lung injury in an animal model of HS/T.
LEVEL OF EVIDENCE: N/A (Basic Science).

DOI: https://doi.org/10.1097/TA.0000000000003487
J Clin Med. 2021 Nov 23. pii: 5484. [Epub ahead of print]10(23):

A Multifunctional, Low-Volume Resuscitation Cocktail Improves Vital Organ Blood Flow and Hemostasis in a Pig Model of Polytrauma with Traumatic Brain Injury.

Alexander E St John, Xu Wang, Kristyn Ringgold, Esther B Lim, Diana Chien, Matthew L Statz, Susan A Stern, Nathan J White.

  The resuscitation of polytrauma with hemorrhagic shock and traumatic brain injury (TBI) is a balance between permissive hypotension and maintaining vital organ perfusion. There is no current optimal solution. This study tested whether a multifunctional resuscitation cocktail supporting hemostasis and perfusion could mitigate blood loss while improving vital organ blood flow during prolonged limited resuscitation. Anesthetized Yorkshire swine were subjected to fluid percussion TBI, femur fracture, catheter hemorrhage, and aortic tear. Fluid resuscitation was started when lactate concentration reached 3-4 mmol/L. Animals were randomized to one of five groups. All groups received hydroxyethyl starch solution and vasopressin. Low- and high-dose fibrinogen (FBG) groups additionally received 100 and 200 mg/kg FBG, respectively. A third group received TXA and low-dose FBG. Two control groups received albumin, with one also including TXA. Animals were monitored for up to 6 h. Blood loss was decreased and vital organ blood flow was improved with low- and high-dose fibrinogen compared to albumin controls, but survival was not improved. There was no additional benefit of high- vs. low-dose FBG on blood loss or survival. TXA alone decreased blood loss but had no effect on survival, and combining TXA with FBG provided no additional benefit. Pooled analysis of all groups containing fibrinogen vs. albumin controls found improved survival, decreased blood loss, and improved vital organ blood flow with fibrinogen delivery. In conclusion, a low-volume resuscitation cocktail consisting of hydroxyethyl starch, vasopressin, and fibrinogen concentrate improved outcomes compare to controls during limited resuscitation of polytrauma.

Keywords:  damage control resuscitation; fibrinogen; hemostasis; multifunctional resuscitation fluid; perfusion

DOI:  https://doi.org/10.3390/jcm10235484
Blood Coagul Fibrinolysis. 2021 Dec 09.

Reduced cleavage of von willebrand factor by ADAMTS13 is associated with microangiopathic acute kidney injury following trauma.

A TACTIC Publication

Acute kidney injury (AKI) is common after trauma, but contributory factors are incompletely understood. Increases in plasma von Willebrand Factor (vWF) with concurrent decreases in ADAMTS13 are associated with renal microvascular thrombosis in other disease states, but similar findings have not been shown in trauma. We hypothesized that molecular changes in circulating vWF and ADAMTS13 promote AKI following traumatic injury. VWF antigen, vWF multimer composition and ADAMTS13 levels were compared in plasma samples from 16 trauma patients with and without trauma-induced AKI, obtained from the Prehospital Air Medical Plasma (PAMPer) biorepository. Renal histopathology and function, vWF and ADAMTS13 levels were assessed in parallel in a murine model of polytrauma and haemorrhage. VWF antigen was higher in trauma patients when compared with healthy controls [314% (253-349) vs. 100% (87-117)] [median (IQR)], while ADAMTS13 activity was lower [36.0% (30.1-44.7) vs. 100.0% (83.1-121.0)]. Patients who developed AKI showed significantly higher levels of high molecular weight multimeric vWF at 72-h when compared with non-AKI counterparts [32.9% (30.4-35.3) vs. 27.8% (24.6-30.8)]. Murine plasma cystatin C and vWF were elevated postpolytrauma model in mice, with associated decreases in ADAMTS13, and immunohistologic analysis demonstrated renal injury with small vessel plugs positive for fibrinogen and vWF. Following traumatic injury, the vWF-ADAMTS13 axis shifted towards a prothrombotic state in both trauma patients and a murine model. We further demonstrated that vWF-containing, microangiopathic deposits were concurrently produced as the prothrombotic changes were sustained during the days following trauma, potentially contributing to AKI development.

DOI: https://doi.org/10.1097/MBC.0000000000001089
Shock. 2021 Dec 03.

Autoresuscitation of Poloxamer 188 in Pigs with Traumatic Severe Hemorrhage.

Wenjun Z Martini, Hui Xia, Irasema Terrazas, Michael A Dubick.

BACKGROUND: Poloxamer 188 (P188) is a copolymer surfactant with plasma membrane stabilizing action. This study investigated the effects of P188 on blood volume and coagulation in pigs after traumatic hemorrhage and hypotensive resuscitation.
METHODS: Femur fracture was performed in 17 anesthetized pigs, followed by hemorrhage of 55% of estimated blood volume and a 10 min shock period. Afterwards, pigs were randomized to be resuscitated with either normal saline (n = 9, 4 ml/kg, NS group) or P188 (n = 8, 1.33 ml/kg at 150 mg/ml, plus 2.67 ml NS/kg, P188 group). Pigs were monitored for 2hrs or until death. Hemodynamics were recorded and blood samples were taken at baseline (BL), after hemorrhage, shock, resuscitation, and at 2hrs for blood and coagulation analysis using Rotem®.
RESULTS: All but one pig in each group survived to 2hrs. Femur fracture and hemorrhage reduced mean arterial pressure to half of the BL and elevated heart rate to double of the BL (both p < 0.05). Resuscitation with NS or P188 did not return these measurements to BL. Compared to NS, resuscitation with P188 resulted in a smaller reduction of blood volume (76 ± 3% in P188 and 60 ± 2% in NS); higher base excess (3.3 ± 0.9 vs. 0.5 ± 0.9 mM); and lower hematocrit (24 ± 1 vs 28 ± 1%) and Ca++ (24 ± 1 vs 28 ± 1 mM). Resuscitation with P188 prolonged aPTT (43 ± 12 vs. 22 ± 3 s, all p < 0.05).
CONCLUSIONS: Following traumatic hemorrhage and hypotensive resuscitation, P188 improved circulation volume and base deficit, but induced slower clotting initiation in pigs. Thus, P188 may have limited benefit as an initial small volume resuscitation adjunct following hemorrhage.

DOI: https://doi.org/10.1097/SHK.0000000000001892
Shock. 2021 Dec 03.

Inhibition of The Interaction Of TREM-1 and eCIRP Attenuates Inflammation and Improves Survival In Hepatic Ischemia/Reperfusion.

Timothy Borjas, Asha Jacob, HaoTing Yen, Vihas Patel, Gene Coppa, Monowar Aziz, Ping Wang.

INTRODUCTION: Triggering receptor expressed on myeloid cells-1 (TREM-1) has important implications in sepsis and inflammation and is a novel receptor for extracellular cold-inducible RNA-binding protein (eCIRP). We hypothesize that the inhibition of TREM-1 via its interaction with eCIRP by novel peptide inhibitor M3 or knockout gene will attenuate the inflammation and injury associated with severe hepatic ischemia/reperfusion (I/R).
METHODS: Wild-type (WT) C57BL/6 and TREM-1-/- mice underwent 60 min of 70% hepatic ischemia, with 24 h of reperfusion. Additionally, WT mice underwent hepatic I/R and were treated with M3 (10 mg/kg BW) or vehicle (normal saline) at the start of reperfusion. Blood and ischemic liver tissues were collected, and analysis was performed using enzymatic assays, enzyme-linked immunosorbent assay, reverse-transcription quantitative PCR, and pathohistology techniques. For survival surgery, mice additionally underwent resection of non-ischemic lobes of the liver and survival was monitored for 10 days.
RESULTS: There was an increase in serum levels of tissue markers including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase as well as cytokine levels (IL-6) and histological scoring of hematoxylin and eosin sections in WT I/R mice. These markers decreased substantially in TREM-1-/- mice. Additionally, neutrophil infiltration markers and markers of local inflammation (myeloperoxidase, macrophage inflammatory protein-2, cyclooxygenase-2) were attenuated in TREM-1-/- mice. Similarly, we show a significant decrease in injury and inflammation markers with M3 treatment. Additionally, we demonstrate decreased apoptosis with TREM-1 inhibition. Finally, M3 treatment improved the survival rate from 42% to 75% after hepatic I/R.
CONCLUSION: TREM-1 is an important eCIRP receptor in the inflammatory response of hepatic I/R, and deficiency of TREM-1 via knockout gene or peptide inhibition attenuated liver injury and inflammation, and improved survival. Inhibition of the TREM-1 and eCIRP interaction in hepatic I/R may have important therapeutic potential.

DOI: https://doi.org/10.1097/SHK.0000000000001894
Anesth Analg. 2021 Dec 09.

Dexmedetomidine Alleviates Gut-Vascular Barrier Damage and Distant Hepatic Injury Following Intestinal Ischemia/Reperfusion Injury in Mice.

Yi-Nan Zhang, Ze-Nan Chang, Zi-Meng Liu, Shi-Hong Wen, Ya-Qing Zhan, Han-Jin Lai, Hu-Fei Zhang, Yi Guo, Xu-Yu Zhang.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) challenge often results in gut barrier dysfunction and induces distant organ injury. Dexmedetomidine has been shown to protect intestinal epithelial barrier against I/R attack. The present study aims to investigate the degree to which intestinal I/R attack will contribute to gut-vascular barrier (GVB) damage, and to examine the ability of dexmedetomidine to minimize GVB and liver injuries in mice.
METHODS: In vivo, intestinal ischemic challenge was induced in mice by clamping the superior mesenteric artery for 45 minutes. After clamping, the mice were subjected to reperfusion for either 2, 4, 6, or 12 hours. Intraperitoneal injection of dexmedetomidine 15, 20, or 25 μg·kg-1 was performed intermittently at the phase of reperfusion. For the in vitro experiments, the challenge of oxygen-glucose deprivation/reoxygenation (OGD/R) was established in cultured vascular endothelial cells, and dexmedetomidine (1 nM) was used to treat the cells for 24 hours. Moreover, in vivo and in vitro, SKL2001 (a specific agonist of β-catenin) or XAV939 (a specific inhibitor of β-catenin) was applied to determine the role of β-catenin in the impacts provided by dexmedetomidine.
RESULTS: The attack of intestinal I/R induced GVB damage. The greatest level of damage was observed at 4 hours after intestinal reperfusion. There was a significant increase in plasmalemma vesicle-associated protein-1 (PV1, a specific biomarker for endothelial permeability) expression (5.477 ± 0.718 vs 1.000 ± 0.149; P < .001), and increased translocation of intestinal macromolecules and bacteria to blood and liver tissues was detected (all P < .001). Liver damages were observed. There were significant increases in histopathological scores, serum parameters, and inflammatory factors (all P < .001). Dexmedetomidine 20 μg·kg-1 reduced PV1 expression (0.466 ± 0.072 vs 1.000 ± 0.098; P < .001) and subsequent liver damages (all P < .01). In vitro, dexmedetomidine significantly improved vascular endothelial cell survival (79.387 ± 6.447% vs 50.535 ± 1.766%; P < .001) and increased the productions of tight junction protein and adherent junction protein (all P < .01) following OGD/R. Importantly, in cultured cells and in mice, β-catenin expression significantly decreased (both P < .001) following challenge. Dexmedetomidine or SKL2001 upregulated β-catenin expression and produced protective effects (all P < .01). However, XAV939 completely eliminated the protective effects of dexmedetomidine on GVB (all P < .001).
CONCLUSIONS: The disruption of GVB occurred following intestinal I/R. Dexmedetomidine alleviated I/R-induced GVB impairment and subsequent liver damage.

DOI: https://doi.org/10.1213/ANE.0000000000005810
NPJ Syst Biol Appl. 2021 Dec 07. 7(1): 44

Personalized modulation of coagulation factors using a thrombin dynamics model to treat trauma-induced coagulopathy.

Damon E Ghetmiri, Mitchell J Cohen, Amor A Menezes.

Current trauma-induced coagulopathy resuscitation protocols use slow laboratory measurements, rules-of-thumb, and clinician gestalt to administer large volumes of uncharacterized, non-tailored blood products. These one-size-fits-all treatment approaches have high mortality. Here, we provide significant evidence that trauma patient survival 24 h after hospital admission occurs if and only if blood protein coagulation factor concentrations equilibrate at a normal value, either from inadvertent plasma-based modulation or from innate compensation. This result motivates quantitatively guiding trauma patient coagulation factor levels while accounting for protein interactions. Toward such treatment, we develop a Goal-oriented Coagulation Management (GCM) algorithm, a personalized and automated ordered sequence of operations to compute and specify coagulation factor concentrations that rectify clotting. This novel GCM algorithm also integrates new control-oriented advancements that we make in this work: an improvement of a prior thrombin dynamics model that captures the coagulation process to control, a use of rapidly-measurable concentrations to help predict patient state, and an accounting of patient-specific effects and limitations when adding coagulation factors to remedy coagulopathy. Validation of the GCM algorithm's guidance shows superior performance over clinical practice in attaining normal coagulation factor concentrations and normal clotting profiles simultaneously.

DOI: https://doi.org/10.1038/s41540-021-00202-9
3 Biotech. 2021 Dec;11(12): 501

Tyrosine kinase nonreceptor 1 (TNK1) knockdown ameliorates hemorrhage shock-induced kidney injury via inhibiting macrophage M1 polarization.

Miaolong Tang, Jimin Cai, Yan Wang, Zhirong Huan, Hao Yao, Ce Xu, Xin Ge, Sheng Song.

  Hemorrhage shock (HS) is a major threat to patients with trauma and spontaneous bleeding, resulting in multi-organ failure including the kidney. Tyrosine kinase nonreceptor 1 (TNK1) has been shown to be upregulated in the kidney of experimental HS and patients with severe trauma. The study aims to investigate the role of TNK1 and the underlying mechanism in HS-induced kidney injury. A model of HS was established with femoral artery bloodletting, followed by resuscitation in Sprague-Dawley rats. Renal expression of TNK1 was abnormally induced by HS in rats. Knockdown of TNK1 alleviated HS-induced cell apoptosis and the level of proinflammatory cytokines (TNF-α, IL-6 and IL-1β) in the kidney. The expression of M1 macrophage markers (CD86 and iNOS) and the activation of STAT1 were inhibited by TNK1 knockdown in HS rats. In vitro, human monocyte THP-1 cells were treated with 20 ng/mL interferon-gamma plus 100 ng/mL lipopolysaccharide to induce M1 polarization. TNK1 knockdown exerted inhibitory effect on macrophage M1 polarization, M1-type inflammatory cytokine production and STAT1 activation in THP-1 cells. In conclusion, downregulation of TNK1 alleviates HS-induced kidney injury by suppressing macrophage M1 polarization, inflammation and kidney cell apoptosis, in which the deactivation of STAT1 signaling may be involved.

Keywords:  Hemorrhage shock (HS); Inflammation; Macrophage M1 polarization; Tyrosine kinase nonreceptor 1 (TNK1)

DOI:  https://doi.org/10.1007/s13205-021-03042-w
Comp Med. 2021 Dec 07.

Hemodynamic Effects of Cardiovascular Medications in a Normovolemic and Hemorrhaged Yorkshire-cross Swine Model.

Jacob H Cole, Scott B Hughey, Phillip G Geiger, Kamala J Rapp-Santos, Gregory J Booth.

The Yorkshire-cross swine model is a valuable translational model commonly used to study cardiovascular physiologyand response to insult. Although the effects of vasoactive medications have been well described in healthy swine, the effects of these medications during hemorrhagic shock are less studied. In this study, we sought to expand the utility of the swine model by characterizing the hemodynamic changes that occurred after the administration of commonly available vasoactive medications during euvolemic and hypovolemic states. To this end, we anesthetized and established femoral arterial,central venous, and pulmonary arterial access in 15 juvenile Yorkshire-cross pigs. The pigs then received a series of rapidlymetabolized but highly vasoactive medications in a standard dosing sequence. After completion of this sequence, each pigunderwent a 30-mL/kg hemorrhage over 10 min, and the standard dosing sequence was repeated. We then used standard statisticaltechniques to compare the effects of these vasoactive medications on a variety of hemodynamic parameters betweenthe euvolemic and hemorrhagic states. All subjects completed the study protocol. The responses in the hemorrhagic state wereoften attenuated or even opposite of those in the euvolemic state. For example, phenylephrine decreased the mean arterialblood pressure during the euvolemic state but increased it in the hemorrhagic state. These results clarify previously poorlydefined responses to commonly used vasoactive agents during the hemorrhagic state in swine. Our findings also demonstratethe need to consider the complex and dynamic physiologic state of hemorrhage when anticipating the effects of vasoactivedrugs and planning study protocols.

DOI: https://doi.org/10.30802/AALAS-CM-21-000080
J Proteome Res. 2021 Dec 07.

Combined Quantitative (Phospho)proteomics and Mass Spectrometry Imaging Reveal Temporal and Spatial Protein Changes in Human Intestinal Ischemia-Reperfusion.

Anna M Kip, Juan Manual Valverde, Maarten Altelaar, Ron M A Heeren, Inca H R Hundscheid, Cornelis H C Dejong, Steven W M Olde Damink, Benjamin Balluff, Kaatje Lenaerts.

  Intestinal ischemia-reperfusion (IR) injury is a severe clinical condition, and unraveling its pathophysiology is crucial to improve therapeutic strategies and reduce the high morbidity and mortality rates. Here, we studied the dynamic proteome and phosphoproteome in the human intestine during ischemia and reperfusion, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to gain quantitative information of thousands of proteins and phosphorylation sites, as well as mass spectrometry imaging (MSI) to obtain spatial information. We identified a significant decrease in abundance of proteins related to intestinal absorption, microvillus, and cell junction, whereas proteins involved in innate immunity, in particular the complement cascade, and extracellular matrix organization increased in abundance after IR. Differentially phosphorylated proteins were involved in RNA splicing events and cytoskeletal and cell junction organization. In addition, our analysis points to mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase (CDK) families to be active kinases during IR. Finally, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MSI presented peptide alterations in abundance and distribution, which resulted, in combination with Fourier-transform ion cyclotron resonance (FTICR) MSI and LC-MS/MS, in the annotation of proteins related to RNA splicing, the complement cascade, and extracellular matrix organization. This study expanded our understanding of the molecular changes that occur during IR in the human intestine and highlights the value of the complementary use of different MS-based methodologies.

Keywords:  human intestinal ischemia−reperfusion; mass spectrometry imaging; phosphoproteomics; proteomics; spatiotemporal data

DOI:  https://doi.org/10.1021/acs.jproteome.1c00447
Nat Commun. 2021 Dec 09. 12(1): 7150

Non-canonical Wnt signaling promotes directed migration of intestinal stem cells to sites of injury.

Daniel Jun-Kit Hu, Jina Yun, Justin Elstrott, Heinrich Jasper.

Tissue regeneration after injury requires coordinated regulation of stem cell activation, division, and daughter cell differentiation, processes that are increasingly well understood in many regenerating tissues. How accurate stem cell positioning and localized integration of new cells into the damaged epithelium are achieved, however, remains unclear. Here, we show that enteroendocrine cells coordinate stem cell migration towards a wound in the Drosophila intestinal epithelium. In response to injury, enteroendocrine cells release the N-terminal domain of the PTK7 orthologue, Otk, which activates non-canonical Wnt signaling in intestinal stem cells, promoting actin-based protrusion formation and stem cell migration towards a wound. We find that this migratory behavior is closely linked to proliferation, and that it is required for efficient tissue repair during injury. Our findings highlight the role of non-canonical Wnt signaling in regeneration of the intestinal epithelium, and identify enteroendocrine cell-released ligands as critical coordinators of intestinal stem cell migration.

DOI: https://doi.org/10.1038/s41467-021-27384-4