Sustainable research activities of ISEM against COVID-19 pandemic
Eiji Kobayashi
The Jikei University School of Medicine

The COVID-19 caused by the novel coronavirus has become a worldwide pandemic
which has persisted for nearly a year and a half. The academic conferences, where
many researches attend, were canceled or postponed, and new measures such as
remote communication methods were adopted in a number of conferences. Thus, theconference organizers were forced to give thought to a new style of communication inthe future.
We are currently unable to attend international conferences due to strict travel
restrictions. Amid such grim situation, there is a remarkable society which crosssectionally connects basic and clinical medicine through microsurgery named theInternational Society for Experimental Microsurgery (ISEM). I would like to introduce
the latest research outcomes of ISEM’s Governance members.
ISEM was initially founded in 1992 by late Professor Sun Lee who introduced
microsurgery into organ transplant research in 1960 and has established a solid1

foundation to organ transplant treatment in the 20th Century by utilizing hisexperimental models. ISEM covers the fields of the basic medicine to clinical medicine,
regardless of type of organ if the topic is related to microsurgery. Although a total
number of members is not large, the members reside all over the world, follow theteachings of Professor Sun Lee, and are interacting like a big family. Every two years
we hold international conference in a different country around the world, and as 10thpresident, I have organized an international conference in Brazil in 2010, supported byProfessor Edna Montero and her colleagues. In 2020, ten years after a conference inBrazil, 15th conference was originally scheduled in Sweden by Congress president
Mihai Oltean and Congress Chair Yelena Akelina and colleagues. Unfortunately, likemany other international conferences, our 15th conference was postponed until thefollowing year. And finally, it will be held online on September 10, 2021:
ISEM | International Society for Experimental Microsurgery www.myisem.org

It is worthwhile saying that ISEM core members are continuously communicating
and now seeking the future conference activities through online discussions.
President Professor Mihai Oltean (Sahlgrenska University Hospital, Sweden) isworking strenuously in various types of organ transplantation such as small bowel

2transplantation (ITx). He reviewed the recent publications pertaining to experimental
ITx and highlighted the main current research topics as the follows (1). During therecent years, ischemia-reperfusion injury (IRI) and Graft-versus-host disease have
gradually replaced acute rejection as the main research topic. New additives toestablished preservation solutions and relatively novel approaches such as luminalinterventions during cold storage may prolong the storage time and alleviate IRI. The
ischemic susceptibility seems to differ between species, which may impact thetranslatability of the experimental findings. A new experimental model of modified
multivisceral transplantation including the donor spleen may offer a new tool with whichto study GVHD, besides the classical Lewis–Brown Norway rat combination. Flushing
the graft with fludarabine may mitigate GVHD in rats. T-cell activation inhibitormitochondrial was downregulated in the peripheral blood leukocytes before other signsof acute and severe chronic rejection could be observed.
Professor Norbert Nemeth (University of Debrecen, Hungary) with Professor Rene
H. Tolba (RWTH Aachan University, Germany) also reviewed experimental IRI
phenomenon which has been associated with adverse clinical outcomes (2). IRI related
tissue damage is characterized by various chronological events depending on the3

experimental model or clinical setting. He introduced that IRI research has been in thespotlight of scientific interest for over three decades with a significant and continuous
increase in publication activity over the years and the large number of pharmacologicaland surgical therapeutic attempts introduced, not many of these strategies have madetheir way into everyday clinical practice. Furthermore, he addressed that
hemorheological factors play an important role in determining tissue perfusion andorchestrating mechanical shear stress-dependent endothelial functions. Antioxidant andanti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation
techniques may improve rheological properties of the post-reperfusion hepatic bloodflow and target endothelial cells, exerting a potent protection against hepatic IRI.
Corresponding Secretary member, Professor Hao Wang (Tianjin Medical University,China) is the head of digestive surgery division, and has been coaching his juniorcolleagues in the basic research area while serving as a mentor of experimental
microsurgery to his fellow colleagues. Professor Wang is also an outstanding
researcher of regenerative medicine, especially in mesenchymal-like endometrial
regenerative cells (ERCs). Using mouse system, they showed that CD73 expression
was critical to ERC-induced attenuation of graft pathology (3). The blockage of CD73

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expression on ERCs was related to the percentage decline of tolerogenic dendritic cells(Tol-DCs), macrophages type 2 (M2), and regulatory T cells (Tregs). As compared with
anti-CD73 mAb pretreated ERCs group, CD73 expressing ERCs significantly increased
the level of anti-inflammatory cytokine IL10 but decreased levels of pro-inflammatory
cytokines including IFN-γ and TNF-α. In addition, CD73 expressing ERCs showedtissue protective function via the regulation of adenosine receptor expression which
was related to the infiltration of CD4+ and CD8+ cells in the allografts. Furthermore,significant increase of A2B receptors in the cardiac allograft was also associated withCD73 expressing ERC-induced prolongation of cardiac allograft survival.
Treasury member, Professor Zheng Jenny Zhang (Northwestern University,U.S.A.) is an expert of organ transplant mouse and rat model, and is a dedicatedresearcher of immunology. Recently, they developed a novel devise of fully implantableand bioresorbable cardiac pacemakers without leads or batteries (4). Temporary
cardiac pacemakers used in periods of need during surgical recovery involve
percutaneous leads and externalized hardware that carry risks of infection, constrain
patient mobility and may damage the heart during lead removal. Then, they developed
a leadless, battery-free, fully implantable cardiac pacemaker for postoperative control

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of cardiac rate and rhythm that undergoes complete dissolution and clearance by
natural biological processes after a defined operating timeframe. They showed thatthese devices provide effective pacing of hearts of various sizes in mouse, rat, rabbit,
canine and human cardiac models, with tailored geometries and operation timescales,
powered by wireless energy transfer.
From Japan, Secretary General Professor Shintaro Yagi (Kanazawa University,Japan) and I advocated the micro- and macro-borderless surgery (MMBS) using anovel high-resolution (4K) three-dimensional (3D) video system. To confirm theapplicability of this concept, we tested the following 3 preclinical experiments (5).
Experiment 1 (non-inferiority test) consisted of dissection and anastomosis of carotid
artery, portal vein, proper hepatic artery, and pancreatoduodenectomy with surgicalloupe versus MMBS. Experiment 2 (feasibility test) consisted of intra-abdominal andintra-thoracic smaller arteries anastomosed by MMBS as a pre-clinical setting.
Experiment 3 (challenge on new surgery) consisted of orthotopic liver transplantation of
the graft from a donor after circulatory death maintained by machine perfusion.
Circulation of the cardiac sheet with a vascular bed in experiment 2 and liver graft
during preservation in experiment 3 was evaluated with indocyanine green

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fluorescence imaging equipped with this system.
I also did my best to generate a functional small intestinalized colon (SIC) by
replacing the native colonic epithelium with ileum-derived organoids using a rat model(6). Organoid technology enables an efficient expansion of intestinal epithelium tissue
in vitro, but reconstruction of the whole small intestine, including the complex
lymphovascular system, has remained challenging. We first found thatxenotransplanted human ileum organoids maintain their regional identity and form
nascent villus structures in the mouse colon. In vitro culture of an organoid monolayer
further revealed an essential role for luminal mechanistic flow in the formation of villi.
We then developed a rat SIC model by repositioning the SIC at the ileocaecal junction,
where the epithelium is exposed to a constant luminal stream of intestinal juice. This
anatomical relocation provides the SIC with organ structures of the small intestine,including intact vasculature and innervation, villous structures, and the lacteal (a fatabsorbing lymphatic structure specific to the small intestine). The SIC has absorptivefunctions and markedly ameliorates intestinal failure in a rat model of SBS, whereastransplantation of colon organoids instead of ileum organoids invariably leads tomortality. These data provide a proof of principle for the use of intestinal organoids for7regenerative purposes, and offer a feasible strategy for SBS treatment.
I have introduced the academic activities of several ISEM members. I hope it
enabled readers to further understand that we the ISEM members, connected bymicrosurgery, are cross-sectionally active in many fields from basic research to clinicalresearch. Furthermore, amid the pandemic, we are committed as academia to fulfill ourduties to overcome COVID-19. Even though the COVID-19 pandemic is prolonged, ourmembers around the world are actively working, at times encouraging each other, tochallenge the current difficulties.

References

1. Oltean M. Intestinal transplantation: an overview of the recent experimental studies. Curr Opin
Organ Transplant. 2021 Apr 1;26(2):240-244. doi: 10.1097/MOT.0000000000000845.
2. Nemeth N, Peto K, Magyar Z, Klarik Z, Varga G, Oltean M, Mantas A, Czigany Z, Tolba RH
Hemorheological and Microcirculatory Factors in Liver Ischemia-Reperfusion Injury-An Update on
Pathophysiology, Molecular Mechanisms and Protective Strategies. .Int J Mol Sci. 2021 Feb
13;22(4):1864. doi: 10.3390/ijms22041864
3. Hu Y, Kong D, Qin Y, Yu D, Jin W, Li X, Zhao Y, Wang H, Li G, Hao J, Zhang B, Pang Z, Wang H. CD73
8expression is critical to therapeutic effects of human endometrial regenerative cells in inhibitionof cardiac allograft rejection in mice. Stem Cells Transl Med. 2021 Mar;10(3):465-478. doi:
10.1002/sctm.20-0154. Epub 2020 Oct 30.

4. Choi YS, Yin RT, Pfenniger A, Koo J, Avila R, Benjamin Lee K, Chen SW, Lee G, Li G,Qiao Y, Murillo-Berlioz A, Kiss A, Han S, Lee SM, Li C, Xie Z, Chen YY, Burrell A, Geist
B, Jeong H, Kim J, Yoon HJ, Banks A, Kang SK, Zhang ZJ, Haney CR, Sahakian AV,Johnson D, Efimova T, Huang Y, Trachiotis GD, Knight BP, Arora RK, Efimov IR,Rogers JA. Fully implantable and bioresorbable cardiac pacemakers without leads orbatteries. Nat Biotechnol. 2021 Jun 28. doi: 10.1038/s41587-021-00948-x. Online
ahead of print.
5. Yagi S, Ito T, Shirai H, Yao S, Masano Y, Ogawa E, Gabata R, Uemoto S, Kobayashi E.
Micro- and macro-borderless surgery using a newly developed high-resolution (4K)
three-dimensional video system. PLoS One. 2021 May 12;16(5):e0250559. doi:
10.1371/journal.pone.0250559. eCollection 2021.
6. Sugimoto S, Kobayashi E, Fujii M, Ohta Y, Arai K, Matano M, Ishikawa K, Miyamoto K,
Toshimitsu K, Takahashi S, Nanki K, Hakamata Y, Kanai T, Sato T. An organoid-based9organ-repurposing approach to treat short bowel syndrome. Nature. 2021
Apr;592(7852):99-104. doi: 10.1038/s41586-021-03247-2. Epub 2021 Feb 24.

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