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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 11  |  Issue : 4  |  Page : 176-181

Histogenesis of human fetal liver with special histochemical and selective immunohistochemical stains


1 Senior Resident, Department of Cytogenetics, Christian Medical College, Vellore, Tamil Nadu, India
2 Assistant Professor, Department of Histopathology, PGIMER, Chandigarh, India
3 Senior Resident, Department of Anatomy, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
4 Additional Professor, Department of Anatomy, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
5 Additional Professor, Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India

Date of Submission26-Aug-2022
Date of Decision28-Sep-2022
Date of Acceptance02-Oct-2022
Date of Web Publication29-Oct-2022

Correspondence Address:
Prabhas Ranjan Tripathy
Room No. 2, Department of Anatomy, Academic Block, All India Institute of Medical Sciences, Bhubaneswar - 751 019, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/NJCA.NJCA_146_22

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  Abstract 


Introduction: The fetal liver cells can differentiate into both hepatocytes and cholangiocytes based on the induction due to clonogenic properties with high growth potential. Understanding liver histogenesis might be helpful in liver and hepatocyte transplantation. Special histochemical and immunohistochemical stains provide better insight into the hepatic cellular architecture, although the literature regarding the same is relatively sparse. Methodology: This study's objective was to document the microscopic structure of the organization of hepatocytes, the appearance of central veins and sinusoids, the formation of the portal triad, and hematopoietic blasts of the liver at various weeks of gestation by using special histochemical and immunohistochemical stains and also to compare our observations with other regions of India and Western countries. Results: It was observed that the central vein and the arrangement of hepatocytes appeared at 14 weeks of gestation. The sinusoids and portal triads were formed at 15 weeks of gestation. The hemopoiesis level in the liver gradually increased from the 14th to 26th week of gestation, after which it decreased. Conclusion: A better understanding of human fetal liver histogenesis will help future research activities in liver transplantation and hepatocyte transplantation from the aborted/stillborn fetal liver from various weeks of gestation.

Keywords: Fetal liver development, hepatogenesis, histogenesis of the liver, immunohistochemistry, special stains


How to cite this article:
Anbarasan A, Mitra S, Kar A, Gaikwad MR, Singh S, Tripathy PR. Histogenesis of human fetal liver with special histochemical and selective immunohistochemical stains. Natl J Clin Anat 2022;11:176-81

How to cite this URL:
Anbarasan A, Mitra S, Kar A, Gaikwad MR, Singh S, Tripathy PR. Histogenesis of human fetal liver with special histochemical and selective immunohistochemical stains. Natl J Clin Anat [serial online] 2022 [cited 2023 Feb 6];11:176-81. Available from: http://www.njca.info/text.asp?2022/11/4/176/359875




  Introduction Top


The human liver started to develop from day 22 of gestation as an endodermal evagination at the foregut's distal end. This evagination, known as a hepatic diverticulum, consists of rapidly proliferating cells, which give rise to ramifying cords of hepatoblasts. Later, they grow to become hepatocytes, hepatic ducts, bile canaliculi of the liver under notch signaling, and other regulatory proteins such as fibroblast growth factor 2 and bone morphogenic proteins.[1],[2] The fetal liver cells can inducibly differentiate into both hepatocytes and cholangiocytes due to clonogenic properties with high growth potential. The understanding of liver histogenesis is essential in transplantation scenarios.

The alternate source for liver transplantation is hepatocyte transplantation. The replacement of just 2%–5% of the liver parenchyma with normal hepatocytes may significantly improve liver function in some metabolic disorders.[3] These hepatocyte-like cells (HLC) can be obtained from induced pluripotent stem cells (iPSCs) and human embryonic stem cells (hESCs). Both these ESCs and iPSCs can amplify without limit and loss of potency. Many studies have shown that the hESCs and human iPSCs (hiPSCs) can differentiate into HLC.[3],[4],[5],[6],[7] If the aborted fetal livers were used for liver transplantation, that would fulfill the demand for organ requirements in the future. By this study, we intend to provide a detailed picture of liver histogenesis in this study with special stains and immunohistochemical markers at various weeks of gestation and also compare our observations with other regions of India and Western countries, which was not done in the previous studies. Furthermore, understanding liver histogenesis would give insight for further clinical research in hepatocyte transplantation from the aborted fetal liver within the cold ischemic time, which contains abundant pluripotent stem cells.[7]


  Materials and Methods Top


The present study was performed on 20 human fetal liver specimens obtained from spontaneously aborted and stillborn fetuses without any gross anomaly from the Obstetrics and Gynecology Department, All India Institute of Medical Sciences, Bhubaneswar. The ethical clearance was received from our institution (IEC/AIIMS BBSR/PG Thesis/2018-19/18), and then, consent was taken from the parents to collect the samples. According to the fetal viability period, these samples were made into two groups, the first group as less than and equal to 24 weeks and the second group as more than 25 weeks of gestation. The first group consisted of 14 samples, in which the 14th week was the lowest, and the second group consisted of six samples [Table 1]. The fetal liver tissue was dissected and removed carefully by severing structures at porta hepatis and made each section from left and right lobes of about 2 cm × 2 cm (length X width) and 1 cm thickness. Then, the tissue was fixed in 10% neutral-buffered formalin and processed for paraffin blocks and the block was cut with the help of a rotary microtome into the size of approximately 3–4 μ in thickness. Then, it was stained with hematoxylin and eosin (H and E) stain, Masson's trichrome stain, reticulin stain, and periodic acid–Schiff stains. For immunohistochemistry, the rabbit monoclonal CK8/CK18 antibody (1:100 dilution) (PathnSitu, Livermore, California) (45-min incubation) for identifying hepatocyte and the mouse monoclonal CD34 antibody (1:100 dilution) (PathnSitu, Livermore, California) (45-min incubation) for identifying endothelial cells and hematopoietic blasts were also performed on these liver sections. Multiple photographs from each case (mean = 20 photos/case/stain) were obtained using the AmScope Microscope Digital Camera and its software. ImageJ software was used for the analysis and objectification of the data. The data thus obtained were correlated with the gestational age, anthropometric measurements, and other baseline characteristics of the fetus. SPSS software version 25 IBM Corporation and its Licensors 1989-2017 (Chicago, IL, USA) was used for statistical analysis of the final data, and graphs were plotted by Microsoft Excel 2019 software.
Table 1: Details of liver tissues collected according to the age of fetus in weeks

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  Results Top


The microscopic pattern of hepatocyte organization

At the 14th week of gestation, the hepatocytes were arranged in clusters. However, by the 15th week of gestation, the formation of a two-cell layer thick plate of hepatocytes was observed [Figure 1].
Figure 1: The histological and immunohistochemical characteristics of hepatocytes organization of the fetal liver at various weeks of development. (a) Masson's trichrome stain of the 14th week of gestation, ×20. (b) CK8 immunopositive hepatocytes of the 15th week of gestation, ×4. (c) Reticulin stain of the 19th week of gestation, ×20. (d) Periodic stain of the 14th week, ×20. CV: Central vein and black arrow show the hepatocytes

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The appearance of the central veins

The central veins started to appear at 14th week of gestation and they were more extensive in diameter initially than in the following weeks of development [Figure 2]. The central vein's average diameter was 225 μ in the first group and 179 μ in the second group of the fetus, which was statistically significant in the Student's t-test (P < 0.001).
Figure 2: The histological and immunohistochemical characteristics of central vein appearance of the fetal liver at various weeks of development. (a) CK8 immunopositive for central vein and hepatocytes at the 14th week of gestation, ×10. (b) CD34 immunopositive for endothelial cells of central vein, ×10. (c) Masson's trichrome stain of the 35th week of gestation, ×10. (d): Hematoxylin and eosin stain of the 40th week, ×4. CV: Central vein, PT: Portal triad

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The formation of the portal triad and its components

The portal triad was not well visualized at the 14th week of gestation, and started appearing at the 15th week of gestation [Figure 3]a and [Figure 3]b. The interlobular bile ducts started appearing at the 17th week of gestation, following which the remodeling began. These ductules were immunopositive for CK8 antibodies in the 19th week [Figure 3]c. Condensation of reticulin fibers around the portal tracts was also noted [Figure 3]d. The endothelial cells of the hepatic artery and portal vein were immunopositive for CD34 antibodies from the 15th week of gestation and continued to remain immunopositive in all groups of gestation of the fetus.
Figure 3: The histological and immunohistochemical characteristics of portal triad formation of the fetal liver at various weeks of development. (a) CD34 immunopositive for endothelial cells of the portal triad at the 15th week, ×10. (b): Masson's trichrome stain of the 17th week of gestation, ×10. (c) CK8 immunopositive for bile ductule in portal triad and hepatocytes at the 19th week, ×10. (d) Reticulin stain of the 25th week of gestation, ×20. PT: Portal triad, BD: Bile ductule

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The appearance of sinusoids

The sinusoids started appearing at the 15th week of gestation and were found to communicate with the central veins [Figure 4]a and [Figure 4]b. The sinusoids were immunonegative for both CK8 and CD34 antibodies in all groups of gestation [Figure 4]c and [Figure 4]d.
Figure 4: The histological and immunohistochemical characteristics of sinusoid appearance of the fetal liver at various weeks of development. (a) Masson's trichrome stain of the 15th week of gestation, ×10. (b) Reticulin stains of 39th week of gestation, ×20. (c) CD34 stains of IHC at the 36th week, ×10. (d) CK8 stains of IHC at the 40th week, ×4. Both (c and d) show immunonegative for sinusoids. PT: Portal triad, CV: Central vein

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Hematopoietic blasts

The islands of hematopoietic elements were abundantly noted from the 14th week of gestation. It increased to attain a maximum level in the 24th week (1.52%), and then, it gradually decreased (0.379%) in the 40th week [Figure 5].
Figure 5: The histological and immunohistochemical characteristics of hematopoietic blasts of the fetal liver at several weeks of development. (a) Hematoxylin and eosin stains at the 14th week of gestation, ×10. (b) Masson's trichrome stain at 19th week, ×10. (c) CD34 stains at 24th week. (d) CD34 stains at the 35th week, ×10. Arrows show the hemopoiesis cells. CV: Central vein, PT: Portal triad

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  Discussions Top


The fetal liver is transitioning from the hematopoietic to the metabolic organ with a change in the vasculature system, maturation of hepatocytes, formation and growth of lobular pattern, and the appearance of the drainage system for bile. The above steps are essential in understanding neonatal jaundice's mechanism in preterm babies, various cholestatic diseases, and harvesting hematopoietic stem cells (HSCs) for various blood disorders. Previous studies have documented the above structure's appearance by using either special stains or with few immunohistochemical markers only [Table 2].
Table 2: The various observations of the histogenesis of the liver in previous studies

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The usage of multiple staining methods and immunohistochemical markers in the present study allowed us to document their appearance and organization precisely. Unlike previous studies, this study included region-wise liver histogenesis comparison between eastern, western, northern, and southern Indian populations. We have included a European country's study also for comparison of liver histogenesis.

In the western Asian population, fetal liver hematopoiesis started to appear at the 6th week of gestation. It gradually decreased from the 32nd week of gestation, as per Albay et al.[14] In contrast, it started to appear in the 7th week of gestation in the western European population and gradually decreased from the 28th week of gestation.[13] In most of the Indian population, studies observed that fetal liver hematopoiesis appeared around the 6th–12th weeks and then gradually decreased from around the 22nd to 36th week of gestation [Figure 6].[8],[9],[10],[11],[12],[15] In our study, the result of the hematopoietic blast was similar to the Indian population studies, as it was observed to appear at the 14th week of gestation and gradually increased till the 24th week, after which it decreased. With the help of ImageJ software, we used the CD34-immunopositive cells to analyze the percentage of the hematopoietic blast of the fetal liver that occurred in several weeks of gestation. The hematopoiesis was noted as 0.9476% at the 14th week of gestation, which was the least age of fetal liver tissue obtained in our study. Then, the cell's blasts gradually increased to a maximum of 1.5204% at the 24th week of gestation. After 24 weeks, it decreased gradually to reach a value of 0.379% at the 40th week of gestation. We applied the Pearson correlation test with this result, which was statistically insignificant because the sample size collected in this study was insufficient. However, future studies with more samples might give a statistically significant result. Since the percentage of hematopoietic cells peaked at the 24th week of gestation, that period of gestation of the fetal liver (stillborn/aborted fetus) can be used as a source for the transplantation of HSCs for various malignant and nonmalignant blood disorders.[16],[17],[18],[19]
Figure 6: Hemopoiesis of fetal liver at various weeks of gestation in previous studies of different regions of India

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The microscopic pattern of hepatocyte organization was observed in several studies. A study by Himabindu and Rao from Visakhapatnam (southern India) region shows that the hepatocyte began to appear after the 10th week of gestation, and in Hashmi and Wankhede study from Maharashtra (western India) region, it was seen around the 7th–10th weeks of gestation.[10],[11] Ansari et al., a study from Marathwada (western India) region and Jaiswal et al. from the Uttarakhand (northern India) region, noted that the hepatocytes started to appear at the 12th week of gestation.[9],[12] Whereas Angadi et al.'s study from Pune (western India) region mentioned that hepatocytes it began to appear between the 12th and 15th weeks of gestation.[8] In the present study, we observed that at the 14th week of gestation (the least age of fetal liver tissue obtained), the hepatocytes were arranged as sheets and irregular cords in the fetal liver. At the 15th week of gestation, they were brick like in structure with a single- or two-cell thickly layered arrangement. Thus, our observation from the present study was correlated to Angadi et al.'s study of the western Indian population. The observations from previous studies indicated that the arrangement of hepatocytes was the earliest in the eastern Indian regions at the 7th–10th weeks, closely followed by southern Indian regions at the 10th week and then western and northern Indian populations at the 12th–15th weeks. This timeline may help to generate hepatocytes from hiPSCs and hESCs. It will be used to treat various hepatic diseases and hepatocyte transplantation.[4],[6]

A previous study by Himabindu and Rao from the southern Indian region showed that the central vein appeared in the early weeks of gestation at the 12th week.[10] In contrast, in the western Indian population, the central vein appeared at the 16th–17th weeks of gestation.[8],[9],[11] The Jaiswal et al.'s study showed that it started appearing after the 22nd week in the northern Indian population.[12] Studies from a western European country (France) indicated that it began to appear in the 10th week of gestation.[13] However, in this study, we observed the central vein at the 14th week of gestation, which was the least age of fetal liver tissue obtained in our study. Although our observation of appearance of central vein was much to the western Indian and northern Indian population studies. Similar to the previous study, the central veins were noted as low-intensity immunoreaction for CD34 in the 14th week.[20] Thus, the observations concluded that the central vein appeared early in the southern Indian population compared to the northern Indian population. In the present study, we observed that the hematopoiesis and the central vein diameter increased in the first group than in the second group. It indicates that the central veins were draining a large blood volume during hematopoiesis in the first group of the fetal liver.

Previous studies of the western Indian population revealed that the portal triad was formed at the 18th week of gestation.[8],[9],[11] In the northern Indian populations, it was formed in the 22nd week, and in the southern Indian region, it was formed in the 12th week, which was the earliest appearance period.[10],[12] In the present study, we observed that the portal triad was formed at the 15th week of gestation, similar to the study of Collardeau-Frachon and Scoazec on the western European population.[13] The portal triad formed earlier in the southern region than in the northern region of India.

In the previous study, the endothelial cells of blood vessels showed immunopositive for CD34 during the 7th and 8th weeks of gestation. Immunoreactivity for endothelium of interlobular vein, artery and their branches in the liver was observed in the middle of fetal development.[20] In our study, the endothelium of interlobular blood vessels was immunopositive for CD34 at the 15th week of gestation. In the present study, the bile ductules showed immunopositive for CK8 (CytoKeratin) antibodies at the 19th week of gestation, whereas in previous studies, it was positive only at the 20th week of gestation.[21] A previous study showed that these human fetal ductal plates can get differentiated into periportal hepatocytes, hepatic stem cells, peribiliary glands, pancreatic acinar-neuroendocrine cells, and biliary ductal cells.[22] In this study, the ductal plate's remodeling started from the hilar to the peripheral direction in the 19th week. The maturation of the biliary tree will be completed by 4–5 weeks after birth. The knowledge of biliary tree development will become beneficial for interpreting biopsies from prematurely born infants.[23]

The sinusoids appeared around the 16th–17th weeks of gestation in the western Indian population.[8],[9],[11] In the southern Indian population, it was observed in the 17th week. Jaiswal et al.'s study shows that it starts seen in the 12th week in the northern Indian population, which was the earliest time of appearance.[12] However, in this study, we have noted that the sinusoids were well visible in the 15th week of gestation, which was correlated with the previous studies in the western Indian population. In an earlier study, the endothelial cells of sinusoids were not immunopositive for CD34, which was the same as the current study.[20] The sinusoids appear first in the northern Indian compared to the southern Indian population.

In a previous study, the liver graft tissue from the 16th week of gestation was used for transplantation in the adult's axillary region, showing the fetal tissue's preimmune and hypoimmune. The posttransplant microscopic features showed that there was no sign of ischemic damage to the graft, and there was no feature of acute transplant rejection. Increased vascularity of the graft and its surroundings was also observed.[24] Being a rich source of primordial stem cells that could proliferate faster, fetal tissue was superior to adult tissue. It can often differentiate in response to the environmental cues around them. The level of histocompatibility antigen in fetal tissue was deficient, so the recipient could not easily reject the graft. It can also reverse the lost function of the host quickly.[25] Hence, aborted/stillborn fetal liver tissue can be used for adult liver transplantation, with which the demand for organ availability can be met if we know the proper timeline for liver histogenesis in various geographical regions.


  Conclusion Top


The present study observed that the central vein and the arrangement of hepatocytes were seen at 14 weeks of gestation. The sinusoids and portal triads were formed at the 15th week of gestation. The level of hemopoiesis in the liver gradually increases from the 14th to 26th week of gestation, and then, it gets decreases from the 26th week. The microscopic structures of the liver, such as hepatocytes, central vein, and portal triad, except sinusoids, were observed earlier in the southern region than in the northern region of India. The sinusoids first appear in the northern Indian population when compared to the other regions of the Indian population. A better understanding of human fetal liver histogenesis will help future research activities in liver transplantation and hepatocyte transplantation source from the aborted/stillborn fetal liver from various weeks of gestation. The usage of multiple staining methods and immunohistochemical markers in the present study allowed us to document their appearance and organization precisely.

Key findings

  • The central vein and hepatocytes were observed at the 14th week of gestation
  • The sinusoids and portal triads were formed at the 15th week of gestation
  • The level of hemopoiesis in the liver gradually increases from the 14th to 26th week of gestation, and then, it gets decreases from the 26th week
  • The sinusoids first appear in the northern Indian population when compared to the other regions of the Indian population. All other microscopic structures of the liver were starts observed earlier in the southern region than in the northern region of India
  • This present study gives a more detailed picture of liver development, which is expected to provide significance for pediatric liver transplantation or hepatocyte transplantation.


Limitations of the study

The total number of fetal livers collected from aborted/stillborn fetuses for this study was 41, but due to gross and microscopic autolysis of tissue, only 20 specimens had preserved microarchitecture under hematoxylin and eosin staining. Out of the 20 specimens, our study's least age of fetal liver tissue was the 14th week of gestation. Hence, we were unable to observe the earlier weeks of liver histogenesis to conclude the appearance of the central vein, the hepatocytes, and the formation of hematopoietic blasts.

Acknowledgments

We would like to acknowledge the faculty members of the Department of Anatomy, AIIMS, Bhubaneswar, India, for their contribution to completing this study on time. We would also like to give special thanks to Dr. Praveen Kumar R for the experimental analysis and also to Mr. Samiur Raheman, senior laboratory technician, AIIMS, Bhubaneswar. The authors also sincerely thank those who donated their fetuses to science so that anatomical research could be performed. Results from such research can potentially increase mankind's overall knowledge which can then improve patient care. Therefore, these donors and their families deserve our highest gratitude.[26]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2]



 

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