Acute liver failure results from massive liver damage over a short period of time. Viral infections (hepatitis B virus), drugs (acetaminophen, halothane), sepsis, Wilson’s disease, or autoimmune hepatitis can all cause acute liver failure, but acute liver failure can be life-threatening. Remember, the liver makes the vast majority of blood proteins such as clotting factors or albumin, and without a functioning liver, multi-organ failure ensues.
Liver transplantation can offer effective treatment of acute liver failure, except that there is a global shortage of available livers. The wife of my colleague at Spring Arbor University waited years and years for a liver until a liver was given to her as the result of a dying declaration. THe need is substantial and the supply is miniscule.
Several experiments have demonstrated that the transplantation of mesenchymal stem cells (MSCs) can treat acute liver failure. Human umbilical cord MSCs (hUCMSCs) can be differentiated into cells that closely resemble liver cells (known as hepatocytes) and these i-Heps, as they are called, display many liver-specific functions (secretion of albumin, storage of glycogen, see Campard et al., Gastroenterology 134 2008: 833-848). Likewise, UBMSCs secrete a host of interesting pro-regenerative molecules that seem to aid in liver recovery, regeneration, and healing when implanted into a damaged liver (see Banas et al., J Gastroenterol Hepatol 24 2009: 70-77; van Poll, et al., Hepatology 47 2008: 1634-1643; Moslem, et al., Cell Transplant 22(10) 2013: 1785-99).
To this end, scientists from the Chinese Academy of Sciences in Shenzhen, China have done an interesting side-by-side comparison of the ability of i-Heps and undifferentiated UCMSCs to mitigate acute liver damage in a mouse model.
Ruiping Zhou and Zhuokun Li in the laboratory of Zhi-Ying Chen and their colleagues injected a mixture of D-Galactosamine and a bacterial compound called LPS (lipopolysaccharide) into the bellies of NOD/SCID mice (non-obese diabetic, severe combined immunodeficiency) to induce acute liver damage. Half of the mice injected with this concoction died of acute liver failure, and autopsies of the mice in these experiments showed that half of the liver cells in their livers had been burned out. A control group was injected with salt solutions and showed no such liver damage.
Of these mice, some of the were injected with either two million UBMSCs or two million i-Heps, six hours after the induction of acute liver damage. The cells were given intravenously, in the tail vein.
Interestingly, both groups of mice – those that had received the UBMSCs and those that had received the i-Heps – showed improved survival and improved liver function as ascertained by several liver function tests. Liver biopsies revealed lower levels of cell death within the liver in both cases. Also when the liver is damaged, there are several blood tests that can reveal the presence of liver damage and indicate the degree of liver damage. In all cases where the D-Galactosamine and LPS were administered, the levels of these liver enzymes increased the first after their administration, but in those animals that received either UBMSCs or i-Heps, the markers of liver damage neither climbed as high, nor did they stay high as long, indicating the damage to the liver was mitigated by the infused stem cells.
Liver biopsies of the laboratory animals further confirmed the decreased levels of liver scarring in those animals that had received the stem cells with the D-galactosamine and LPS. Also the levels of cell division, indicative of healing, were increased in the stem cell-treated animals. Two weeks after the initial liver damage, large areas of the liver were observed that showed the signs of cell division, which indicates the presence of active liver repair activities at work in the stem cell-treated animals. Mice not treated with stem cells showed extensive liver damage with little signs of healing if they survived at all.
This interesting study shows that both hUCMSCs and hUCMSC-derived -i-Heps exhibited similar therapeutic effects for mouse acute liver failure. Also, when injected into the tail vein, the stem cells were able to home to the damaged liver and set up shop there. The liver regeneration in both cases seemed to be due to the stimulation of resident liver cells rather substantial contributions from the infused stem cells.
What does this mean for human regenerative medicine? Umbilical cord MSCs are probably a good source of material to treat liver failure. However, such cells will need to be matched to the tissue type of the patient. Secondly, a point emphasized in this paper is that MSCs should not be overly manipulated before they are used because some experiments with MSCs have shown that if these cells are grown in long-term culture, they can undergo malignant transformation (see Rosland, et al., Cancer Res 69 2009: 5331-5339).
Thus beefing the number of cells up for therapeutic purposes to treat a human, which is larger than a mouse, might represent a challenge. However, it is possible to expand MSCs in culture without transforming them into cancer cells, as long as it is done for a short period of time. Finally, MSCs represent an excellent alternative for the shortage of livers, since they can stimulate the liver’s internal healing systems to heal themselves on a short-term basis without the need for a liver transplantation. This sounds like a win-win situation. Of course more work must be done first. Preclinical studies like this must be expanded and then larger animals will need to be used as well before human clinical trials can be planned.