Role of Heme Oxygenase-1 in Postnatal Differentiation of Stem Cells: A Possible Cross-Talk with MicroRNAs

Abstract

Significance: Heme oxygenase-1 (HO-1) converts heme to biliverdin, carbon monoxide, and ferrous ions, but its cellular functions are far beyond heme metabolism. HO-1 via heme removal and degradation products acts as a cytoprotective, anti-inflammatory, immunomodulatory, and proangiogenic protein, regulating also a cell cycle. Additionally, HO-1 can translocate to nucleus and regulate transcription factors, so it can also act independently of enzymatic function. Recent Advances: Recently, a body of evidence has emerged indicating a role for HO-1 in postnatal differentiation of stem and progenitor cells. Maturation of satellite cells, skeletal myoblasts, adipocytes, and osteoclasts is inhibited by HO-1, whereas neurogenic differentiation and formation of cardiomyocytes perhaps can be enhanced. Moreover, HO-1 influences a lineage commitment in pluripotent stem cells and maturation of hematopoietic cells. It may play a role in development of osteoblasts, but descriptions of its exact effects are inconsistent. Critical Issues: In this review we discuss a role of HO-1 in cell differentiation, and possible HO-1-dependent signal transduction pathways. Among the potential mediators, we focused on microRNA (miRNA). These small, noncoding RNAs are critical for cell differentiation. Recently we have found that HO-1 not only influences expression of specific miRNAs but also regulates miRNA processing enzymes. Future Directions: It seems that interplay between HO-1 and miRNAs may be important in regulating fates of stem and progenitor cells and needs further intensive studies.

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

“…176 For example, expression of HO-1 in myoblasts downregulated specific miRs ( e.g., miR-1, miR-133a/b, and miR-206) associated with the inhibition of myoblast differentiation. 177 Expression of HO-1 in tumor cells was associated with downregulation of miR-378.…”

Modulation of Antiviral Immunity by Heme Oxygenase-1

“…13 In addition, HO-1 expression is also regulated in a posttranscriptional manner by miRNAs. 14 Indeed, studies performed in the context of an intravascular hemolysis model, showed that miR-377 and miR-217 interact with the Hmox1e3 0 -untranslated region, resulting in the reduction of HO-1 protein expression and, hence, reduced enzymatic activity. 15 Furthermore, miR-122, which is a miRNA highly expressed in the human liver, also down-regulates HO-1 expression.…”

Heme Oxygenase-1 and Carbon Monoxide in the Heart

“…This study demonstrated that CO-mediated mitochondria biogenesis is a crucial step in the maturation of embryonic stem cells into energetically efficient cardiomyocytes, 202 providing additional evidence on the emerging and perhaps crucial role of the HO-1 pathway in the control of energetic metabolism not only in cardiac tissue but also during stem cell differentiation. 203 …”