Liver cell therapies: cellular sources and grafting strategies

doi:10.1007/s11684-023-1002-1

Front. Med.

2023, Vol. 17

Issue (3) : 432-457 https://doi.org/10.1007/s11684-023-1002-1

REVIEW

Liver cell therapies: cellular sources and grafting strategies

Wencheng Zhang^1,^2,³, Yangyang Cui^1,^2,^3,⁴, Yuan Du^1,⁵, Yong Yang^1,⁵, Ting Fang^1,^2,³, Fengfeng Lu^1,^2,³, Weixia Kong⁶, Canjun Xiao⁷, Jun Shi^5,⁷, Lola M. Reid⁸(

), Zhiying He^1,^2,³(

)

¹. Institute for Regenerative Medicine, Ji’an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, China
². Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, China
³. Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China
⁴. Postgraduate Training Base of Shanghai East Hospital, Jinzhou Medical University, Jinzhou 121001, China
⁵. The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
⁶. Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, 565-0871, Japan
⁷. Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an 343006, China
⁸. Department of Cell Biology and Physiology and Program in Molecular Biology and Biotechnology; UNC School of Medicine, Chapel Hill, NC 27599, USA

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Abstract

The liver has a complex cellular composition and a remarkable regenerative capacity. The primary cell types in the liver are two parenchymal cell populations, hepatocytes and cholangiocytes, that perform most of the functions of the liver and that are helped through interactions with non-parenchymal cell types comprising stellate cells, endothelia and various hemopoietic cell populations. The regulation of the cells in the liver is mediated by an insoluble complex of proteins and carbohydrates, the extracellular matrix, working synergistically with soluble paracrine and systemic signals. In recent years, with the rapid development of genetic sequencing technologies, research on the liver’s cellular composition and its regulatory mechanisms during various conditions has been extensively explored. Meanwhile breakthroughs in strategies for cell transplantation are enabling a future in which there can be a rescue of patients with end-stage liver diseases, offering potential solutions to the chronic shortage of livers and alternatives to liver transplantation. This review will focus on the cellular mechanisms of liver homeostasis and how to select ideal sources of cells to be transplanted to achieve liver regeneration and repair. Recent advances are summarized for promoting the treatment of end-stage liver diseases by forms of cell transplantation that now include grafting strategies.

Keywords liver regeneration hepatocytes cholangiocytes stem cells organoids regulatory mechanisms transplantation/grafting strategies

Corresponding Author(s): Lola M. Reid,Zhiying He

Just Accepted Date: 05 June 2023 Online First Date: 30 June 2023 Issue Date: 28 July 2023

Cite this article:

Wencheng Zhang,Yangyang Cui,Yuan Du, et al. Liver cell therapies: cellular sources and grafting strategies[J]. Front. Med., 2023, 17(3): 432-457.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1002-1
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I3/432

Fig.1 Intra-hepatic cell sources for cell therapies for the liver. (A) Stem cells and hepatic parenchymal cells contribute slowly to the liver’s natural turn-over through a mix of hyperplastic and hypertrophic responses. In the liver parenchyma, maturation of cells occurs along the liver plates from zone 1 to zone 3, with diploid cells existing in zone 1 and transitioning to polyploid ones that become dominant in zone 3. The extent of polyploidy varies with the species. Humans have hepatocytes that are mostly diploid with a minor proportion of tetraploid cells in zone 3 in adults. Rats and mice are the opposite with zones 2 and 3 hepatocytes being entirely polyploid, even in young adults. Mice are the most extreme in that even in a young adult, half of the cells in zone 1 are polyploid; those in zone 2 are tetraploid and octaploid; and those in zone 3 are up to 32N. (B) Shown of the horizontal view of ductal structures of periportal and pericentral area of the liver acinus. Hepatocytes marked as blue near the periportal zone (zone 1) are detected as E-cadherin⁺; the ones marked as green in the pericentral zone (zone 3) are glutamine synthetase⁺ (GS⁺). At the end of zone 3, there is a single layer of diploid pericentral hepatocytes, which was described as Axin2⁺ cells are diploid, are attached on their lateral borders with junctions to endothelia of the central vein, have unique gene expression; and have been found to replace dead and dying polyploid hepatocytes. Abbreviations: PV, portal vein; HA, hepatic artery; BD, bile duct; CV, central vein; BTSCs, biliary tree stem cells; hHpSCs, human hepatic stem cells; Axin2, axis inhibition protein 2; GS, glutamine synthetase; E-cad, E-cadherin.

Fig.2 Extrahepatic stem/progenitor cell sources for cell therapies for the liver. (A) The ultimate sources of stem cell populations for liver and pancreas are in the peribiliary glands (PBGs) attached to extramural (B) or within the walls of intramural (C) bile ducts and found throughout the biliary tree, especially in the hepato-pancreatic common duct, and the large intrahepatic bile duct and with late-stage ones in the gallbladder that has no PBGs. There is a recent study that has revealed another branch of the network, stem cell populations in the submucosa of duodenum, the Brunner’s glands (D). The intramural populations are well-characterized co-hepato/pancreatic stem cell sources for the regeneration of liver and pancreas. (E) A summary table of the abundance of peribiliary glands in the biliary tree system is presented in the Figure. Abbreviations: IHBD, intrahepatic bile duct; GB, gallbladder; AD, accessory (pancreatic) duct; HPCD, hepato-pancreatic common duct; dSGSCs, duodenal submucosal gland stem cells; PV, portal vein; HA, hepatic artery; BD, bile duct; CV, central vein.

Fig.3 Schematic of the entire network plus the transcription factor and gene listing for the stem cell niches in the extramural PBGs, the duodenal submucosal gland stem cells, intramural PBGs, and the gallbladder.

Fig.4 Signature traits of the various stages of cells in the biliary tree, the hepatic lineage and the pancreatic lineage. The biliary tree stem cell populations give rise to the last lineage stages of stem cells for the liver, hepatic stem cells and their descendants, hepatoblasts, located in or next to the canals of Hering (zone 1). Under quiescent conditions, they undergo slow proliferation and maturation to give rise to mature hepatocytes and cholangiocytes within the liver plates. Their speed of regeneration increases dramatically with injury to the liver. Current known markers of hepatic stem cells include a modest level of expression for pluripotency genes (e.g., OCT4, SALL4, BMI-1), hepatic transcription factors (SOX9, SOX17, HNF4A), and surface markers (EpCAM, LGR5, NCAM and CD44); those for the hepatoblasts are the same as for hepatic stem cells with the caveats that NCAM is replaced by ICAM1, and the hepatoblasts express high levels of alpha-fetoprotein.

Fig.5 Transplantation methods for cell therapy of liver diseases. Currently reported transplantation methods for liver are compared. These include direct injection (with and without hyaluronan coating of the cells), vascular delivery (most commonly through intrasplenic injections), cell sheet engineering, and patch grafting. (A) Direct injection is not successful given the adverse mechanical effects and the inefficient ability of the cells to become vascularized. These difficulties are alleviated partially by injecting the cells with a hyaluronan coating, since the liver’s propensity for clearance of hyaluronans facilitates engraftment and keeps the cells localized to the desired target site. This “injection grafting” method can accommodate only relatively small numbers of cells. (B) Vascular delivery is the most commonly used method currently for cell transplantation. However, the percentage of cells that successfully engraft is low: approximately 20% for mature hepatocytes and 5% or less for stem cells. Additional difficulties are the propensity to form life-threatening emboli and to have cells distributing to ectopic sites. (C) Cell-sheet engineering provides a sheet of hepatocytes formed ex vivo on thermolabile culture dishes, released from the dishes, and then transferred to the surface of the liver. The cells can function to provide requisite functions that do not require extensive interactions with other cells of the liver for regulation. These cell sheets remain at the surface, do not integrate within the liver, and so are limited both in the numbers of cells transferable as a sheet and without the ability to interact with all of the cells of the liver. Therefore, they are restricted in their ability to overcome liver deficits or pathologies. (D) Patch grafting involves transplantation of organoids of endodermal stem/progenitors partnered with angioblasts and precursors to endothelia and stellate cells. Mature cells, that are hepatocytes or cholangiocytes, will not engraft at all unless partnered with mesenchymal stem cells (MSCs) and even with that partnership will engraft only partially as successfully as do the organoids of stem cells. For both the organoids and for the mature cells plus MSCs, the donor cells are embedded in a very soft hyaluronan hydrogel that is placed on the surface of the organ, covered with a backing of silk impregnated with a more rigid hyaluronan hydrogel, and the graft tethered to the surface of the liver. Note: the backing, theoretically, could also be amnion or omentum instead of the hyaluronan-infused silk. This now must be considered, since the silk product has been discontinued and is no longer available. There are multiple forms of amnion-derived matrix available commercially and are already in use in clinical programs of grafting. The conditions of the graft enable the stem/progenitors in the organoids (or the mixtures of hepatocytes and MSCs) to produce matrix metalloproteinases, especially secreted isoforms, that enable organoids (or cell suspensions) to engraft through the Glisson’s capsule, and then into and throughout the liver. This occurs rapidly, within a week. Clearance of the hyaluronans in the graft’s biomaterials results in donor cells regulatable by the organ-specific synergistic effects of soluble signals and extracellular matrix components to mature into adult fates. This occurs in parallel with the engraftment and integration process and so is rapid. The entire engraftment and then maturation process occurs within approximately two weeks. The several grafting techniques (injection grafting, cell sheet engineering, and patch grafting) are efforts to overcome the low engraftment efficiency, ectopic cell distribution and high propensity to form emboli, risks that occur with vascular infusion, in current clinical procedures. Abbreviations: PV, portal vein; CV, central vein.

Tab.1 Summary of clinical trials of stem cells (other than MSCs) in the cell therapies for liver diseases^a

Fig.6 The homeostasis maintenance and cellular repair after cell transplantation via vascular delivery. (A) Under physiologic conditions, the majority of hepatocytes are quiescent with a rare portion of them transitioning into a mitotic phase. The slow turnover is regulated by growth factors or other signals from quiescent hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), and Kupffer cells (KCs). (B) Upon the transplantation, the hypoxia due to sinusoidal ischemia can activate endothelial cells to promote the anchoring of transplanted cells to the sinusoidal endothelial cells via adhesion molecules and hyaluronan receptors. Then, cytokines such as interleukins and tumor necrosis factor-α affect endothelial cells to provide perisinusoidal space to allow the transplanted cells to enter the liver plate. Factors such as IGF2 released by damaged hepatocytes can recruit the transplanted cells to the damaged spot, which eventually promote the engraftment of transplanted cells/hepatocytes.

Fig.7 Cellular repair and the regulatory mechanisms during acute and chronic liver injury. (A) The macrophages in the bone marrow are rarely activated under healthy conditions. Following acute and limited insults, liver regeneration is rapidly activated, and Kupffer cells act as guards and sensors of DAMPs, released by apoptotic hepatocytes. CSF1 (colony stimulating factor 1) serves as a potent chemokine and can recruit plentiful bone-marrow-derived monocytes to replenish the loss of resident liver macrophages and exert its proinflammatory role in this process. Those monocytes have a high potential to differentiate into a Ly6C^– subtype involved in liver repair. Meanwhile, LSECs (liver sinusoidal endothelial cells) act as a gatekeeper of HSCs (hepatic stellate cells) and secrete HGF to promote hepatocyte proliferation. Due to the nitrogen oxide (NO)-dependent pathway, HSCs remain quiescent and produce limited extracellular matrix (ECM). (B) Upon chronic liver injury, due to the inhibition of the NO-dependent pathway, LSEC loses its function as a gatekeeper, and HSC is activated into myofibroblasts that produce a huge amount of extracellular matrix. Moreover, the chronic injury can result in continuous proliferation of hepatocytes and unbalanced heterozygosity of the diploid hepatocytes, resulting in a higher risk of hepatocytes undergoing oncogenesis resulting in hepatocellular carcinomas (HCC).

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