Current Perspectives Regarding Stem Cell-Based Therapy for Liver Cirrhosis

Resumo
Liver cirrhosis is a major cause of mortality and a common end of various progressive liver diseases. Since the effective treatment is currently limited to liver transplantation, stem cell-based therapy as an alternative has attracted interest due to promising results from preclinical and clinical studies. No entanto, there is still much to be understood regarding the precise mechanisms of action. A number of stem cells from different origins have been employed for hepatic regeneration with different degrees of success. The present review presents a synopsis of stem cell research for the treatment of patients with liver cirrhosis according to the stem cell type. Clinical trials to date are summarized briefly. Finalmente, questões a serem resolvidas e perspectivas futuras são discutidas em relação às aplicações clínicas.

1. Introdução
   A fibrose hepática resulta de lesão sustentada, que pode ser infligida por vários fatores, como vírus, drogas, álcool, doenças metabólicas, e ataques autoimunes [1]. A exposição prolongada a esses fatores prejudiciais causa apoptose de hepatócitos, recrutamento de células inflamatórias, comprometimento das células endoteliais, e, por último, ativação de células estreladas hepáticas, as principais células envolvidas na fibrose hepática. A fibrose hepática é um tipo de formação de tecido cicatricial em resposta a danos no fígado [2–9]. Histologicamente, é causado por um desequilíbrio entre a síntese e degradação da matriz extracelular [10–12].

A cirrose hepática é uma condição em que o tecido cicatricial substitui o tecido saudável do fígado e nódulos regenerativos com faixas fibrosas circundantes se desenvolvem como resultado da lesão. [13]. A cirrose é o fim comum da doença hepática progressiva de várias causas, resultando em insuficiência hepática crônica, acarretando complicações como encefalopatia hepática, peritonite bacteriana espontânea, ascite, e varizes esofágicas [14]. Infelizmente, a maioria dos casos geralmente está em um estado irreversível quando diagnosticado. Apesar dos avanços atuais em sua gestão [15, 16], a cirrose foi a 14ª principal causa de morte no mundo em 2012 [17]. O transplante ortotópico de fígado é conhecido por ser a única solução definitiva para a cirrose terminal.

No entanto, vários problemas impedem a aplicação predominante do procedimento, including immunological rejection and the scarcity of donor sources [18].

Na verdade, the liver has an inherent regenerative capacity to a substantial degree [19], e, thus, the cessation of those harmful factors may prevent further progression of fibrosis and reverse the situation in some cases [20]. In cases where hepatocyte proliferation is insufficient for recovery from liver injury, bipotent resident liver progenitor cells (LPC) are activated and participate in liver regeneration by differentiating into hepatocytes and biliary epithelial cells [19, 21–23]. No entanto, fibrosis is inevitable when regeneration is exceeded by destruction. Clinical signs of liver failure usually appear after about 80 para 90% of the parenchyma has been destroyed.

Hepatocyte transplantation has been proposed as an alternative approach to transplantation, since hepatocytes have been proven to be strongly associated with liver repair [24–28]. While hepatocyte transplantation is safe in humans, its applicability remains limited due to organ availability, failure of donor engraftment, weak viability in cell culture, and vulnerability to cryopreservation damage [25, 26, 29–32].

Instead of hepatocytes, the transplantation of stem cells has shown therapeutic potential for liver function improvement according to recent experimental studies and human studies [20, 26, 33–40]. Although they remain unclear, the major potential mechanisms have been proposed as a twofold; one is the improvement of the microenvironments through paracrine effects, and the other is the replacement of functional hepatocytes [20].

To date, several kinds of stem cells have been investigated for their therapeutic feasibility and clinical potential in liver cirrhosis [41–43]. The present article briefly reviews the current literature according to the types of stem cells and discusses the future perspectives of stem cell-based therapy in liver cirrhosis.

2. Sources of Stem Cells
   Hepatocytes obtained via autopsy of patients who received bone marrow transplantation suggested that they are pluripotent cells in bone marrow [44, 45]. Atualmente, at least three types of bone marrow-derived cells are known to differentiate into hepatocyte-like cells (HLCs): células-tronco hematopoéticas (HSCs), células-tronco mesenquimais (MSC), and endothelial progenitor cells (EPCs), though early infusion trials did not discriminate the origins of those cells from bone marrow-derived stromal cells with some improvement [32, 46–52]. A large number of preclinical studies have proven the feasibility of HSCs, MSC, and EPCs to restore hepatic function in models of liver injury [53–57]. Além disso, other stem cells including embryonic stem cells (CES) e células-tronco pluripotentes induzidas (iPSCs) can also be differentiated into HLCs [58–60]. HLCs can contribute to the remodeling of cirrhotic liver [20, 61–68].